(1)
Clinical Department, Urals Research Centre for Radiation Medicine, Chelyabinsk, Russia
Abstract
Diagnosing CRS is often a complicated task, especially when no data on the individual organ doses are available. The greatest difficulties of diagnosing CRS arise in mild cases of the syndrome, when non-specific predominantly functional changes in critical organs (hematopoiesis, immunity, and nervous system) develop. It is important to take into consideration the fact that CRS is a threshold effect and can have a long-term latency period. The major criterion of the CRS is a clear-cut dependence of the dynamics of the number of leukocytes, neutrophils and thrombocytes in the peripheral blood on the dose rate to RBM, and in case of a long-term exposure – on annual dose rates to RBM. In diagnosing CRS it is necessary to take a due account of the long-term influence of non-radiation factors (chemicals, stress, etc.) and to make differential diagnosis with a large group of diseases that have clinical manifestations similar to those of the CRS (hematological diseases, diseases of the nervous system, infectious diseases, etc.).
To date, many radiation-induced effects in humans present a serious problem in terms of diagnosis. In case the source of radiation exposure is not obvious, making a diagnosis of radiation damage may frequently become challenging. In the recent years, the problem of attributability, the ability to attribute medical–biological effects to radiation exposure, is highly relevant. The problem is of highest relevance to stochastic effects (carcinogenic and inheritable) and of great significance for identifying the causal relationship between the disease and radiation exposure. Attribution still remains a subjective process which is implemented by physicians attributing certain health effects to radiation exposure. The diagnostics and attributability of radiation effects present a difficulty since no specific biological markers of radiation-related diseases have been identified so far. Identification of such markers would considerably improve diagnostics and the procedure of attribution. However, today it has already become possible to use the techniques allowing attribution of malignant tumors to chemical substances (EPA 1999), or to UV radiation (Brash et al. 1991), thus reducing the possibility of attributing them to IR.
It is known that tissue reactions to acute exposure at high doses occur rather soon and, therefore, can be diagnosed in an exposed person by experienced specialists without serious problems. Acute exposure at high doses induces all the damage within a relatively short period of time. In such cases, it is important to determine the causal relationship between clinical effects and radiation exposure. For example, distinct signs of ARS, manifested soon after the exposure, can be easily enough diagnosed as radiation-related damage by an expert on the basis of the relationship between the high doses of acute radiation exposure and the effects observed.
Radiation exposure within a range of intermediate to high doses for a long time period (several weeks–months–years) at low dose rates results in a delayed damage. Such tissue reactions cannot always be unequivocally associated with radiation exposure, and making a clinical diagnosis may cause considerable problems in such cases. Thus, under exposure to high doses, there exists a direct evidence of a cause-and-effect relationship, whereas under chronic exposure such a relationship is not, as a rule, unequivocal.
7.1 Basic Principles Applied in Diagnosing CRS
Traditionally, the diagnosis of a disease is based on the analysis of the clinical picture, identification of its principal manifestations (symptoms), and ascertainment of the etiology of the disease. As it has been mentioned above, CRS has no specific clinical symptoms, and, therefore, all the accompanying circumstances and factors should be taken into account. In order to make a correct diagnosis of CRS, it is of paramount importance to take into consideration the following characteristics:
Dose threshold.
Latency period.
Degree of severity of the condition is determined by the dose and dose rate to critical organs. Dose rate plays a definitive role.
Character of the disease course is determined by the dynamics of dose rates of exposure received to critical organs.
Individual radiosensitivity.
Need for taking into account non-radiation factors.
Requirement for a differential diagnosis.
7.1.1 Clinical Presentation
As described in detail in Chap. 5, the clinical picture of CRS displayed by the inhabitants of the Techa riverside villages in the period of syndrome formation had no pathognomonic symptoms; however, the sequence of the development and regress of the symptoms is unique, and it is determined mainly by the exposure dose rates absorbed into the critical organs (hematopoietic system, nervous system, and bone tissue). The dose rates determine the intensity of functional and morphological changes in hematopoietic, nervous, and other systems, as well as clinical symptoms of the syndrome which should be taken into account in making the diagnosis of CRS.
The individual radiosensitivity of tissues (organs) and the patterns of dose rate distribution among organs determine the sequence of CRS symptom development. A gradual development of the clinical symptoms is typical of the syndrome. As is indicated above, originally, exposed persons were noted to develop functional changes in the hematopoietic system (neutropenia and thrombocytopenia), vegetative dysfunction, and then asthenic symptoms which under the conditions of continuing exposure were aggravating and assumed a chronic form. Anemia which was the first to develop was followed by obvious manifestations of BM hypoplasia, organic damages to CNS, and ostealgic syndrome, all of which were progressing due to the continuing exposure. It is important to note that disorders of the sense of smell and touch, as well as immunity disorders, can often precede the development of a full clinical picture of the syndrome, a fact that should alert the physicians and experts who are following up patients exposed to IR sources (Akleyev and Kisselyov 2001).
The diagnosis of CRS even if it is caused by external γ-radiation quite often presents great difficulties, to say nothing of the cases of combined external and internal exposure. Special difficulties arise when CRS is at an early stage of its development when mainly nonspecific functional disorders are manifested by a number of organs and systems. Thus, it is important to emphasize that the most important diagnostic criteria of CRS in adults are changes in hematopoiesis (neutropenia and thrombocytopenia). The degree of deficit of mature neutrophilic granulocytes and thrombocytes in the peripheral blood characterizes the degree of CRS severity and clinical course of the syndrome. According to AK Guskova, the functional and morphological changes in the structure of these cells are rather secondary in nature (Barabanova et al. 2007).
As a rule, dynamic assessment of complete blood counts and BM investigations (for medical indications) are sufficient for detecting radiation-induced hematological changes. GD Baysogolov (1961) considered the level of blood neutrophilic granulocytes and thrombocytes to be the most reliable criterion in diagnosing CRS. Partial analyses of myelograms allow assessment of early functional changes in the RBM in cases of CRS of moderate and low severity (Akleyev and Varfolomeyeva 2007; Akleyev and Varfolomeyeva 2007) and morphological changes (BM hypoplasia).
Examination of the nervous system consists of the assessment of the reflex activity, motor activity, sensory sphere (vision, hearing, taste, sense of smell), and cranial nerve sensitivity and functions (Guskova 1960; Ilyin 1985). Assessment of the reflex activity involves verification of the presence or absence of a reflex, its symmetry, occurrence time, reflex response strength, and correlation with age in children. Assessment of the motor sphere status includes examination of the passive and active movements (three-dimensional active movements, motor status, and muscle strength).
Neurological examinations of exposed individuals, in case CRS is suspected, should include examination of the eyeground, the use of electrophysiological methods of examination (electroencephalography in dynamics, induced potentials, electroneuromyography of the extremities), ultrasonic methods (echoencephalography, ultrasonic dopplerography examination of vessels of extremities, rheovasography, and rheoencephalography), and thermography. In order to assess the blood flow in the brain vessels, it is also recommended to apply transcranial dopplerography. The induced potentials, both auditory and vestibular, help assess the acoustic nerve damage, so they also play an important role in assessing the vestibular portion of the cranial nerve. If required, magnetic resonance imaging (MRI) and positron emission tomography (PET) can be used. Evaluation of the vibration sensitivity in the extremities is recommended for early detection of polyneuropathy. No less informative are vegetative tests (orthostatic test, epigastric test, and Aschner’s oculocardiac reflex); assessment of dermographism, hyperhidrosis, and urination; and other tests.
Taking into account the osteotropicity of 90Sr and its predominant distribution in the mineral part of the patients’ bones, it would be advisable to measure the contents of phosphorus and calcium in the blood serum. To assess the functional status of bone tissue, it is recommended to measure bone-specific alkaline phosphatase (ALP). Its presence in the blood serum of healthy adults is indicative of osteogenesis activation. The increased osteogenic activity can be confirmed by the increased excretion of oxyproline with urine (Ilyin 1985). X-ray or ultrasonic examinations, as well as computer-aided tomography and densitometry, are performed based on medical indications.
Critical organs in case of exposure to 239Pu are the liver, bones (skeleton), and lungs in case of inhalation intakes. The changes in the liver and lungs can be identified based on a decrease in serum albumins and an increase in γ-globulins, protein-bound hexoses, hexosamines, sialic acids, and LDH isoenzymes (LDH3). The functional status of the liver can be assessed taking into account the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as well as an increase in the normal and occurrence of pathological hepatic isoenzymes of ALP.
In case of 235U intakes, the basic toxic effect is related to kidney damage; therefore, the follow-up of such patients should involve assessment of the functional status of their kidneys: the levels of residual nitrogen, urea, potassium, ALP, and LDH. In case of 137Cs intakes with its predominant distribution within muscles and parenchymatous organs, it is advisable to measure serum enzymes of muscular origin (AST, creatine kinase, LDH, and its isoenzymes) and also creatinine and creatine excretion levels. In order to assess the thyroid gland status, it is recommended to estimate the levels of protein-bound iodine and thyroid hormones in the blood serum (Ilyin 1985).
In order to diagnose vegeto-vascular dystonia syndrome, it is advisable to use electrocardiography, echocardiography with dopplerography of the large vessels, MRT, polycardiography, rheoencephalography, and rheovasography.
The diagnostic techniques that can help make an early diagnosis of pneumofibrosis include computer-assisted tomography, roentgenography, and examination of the respiratory function.
In cases of ostealgic syndrome in zones of tenderness, vibration sensitivity is examined, and it is recommended to perform rheovasography.
Ophthalmologic examination includes assessment of the anterior chamber of the eye and its appendages, eidoptometry, measurement of intraocular pressure, examination of the refractive media of the eye, biomicroscopy of the crystalline lens, ophthalmoscopy, and measurement of the diastolic pressure in the central artery of the retina (Ilyin 1985).
Evaluation of the immune status should be aimed at assessment of the adaptive immunity, primarily of the cell immunity, measurement of the level of proinflammatory cytokines, and assessment of the innate immunity: natural cytotoxicity, mononuclear phagocyte system, and especially of neutrophilic granulocytes (UNSCEAR 2009).
The diagnosis of CRS is made on the basis of patient’s clinical symptoms and findings of laboratory investigations characteristic of the syndrome (changes in the hematopoietic, nervous, immune, cardiovascular, and endocrine systems and digestive organs) and also taking into account the dosimetry data. The symptom complex can be complete or not quite complete, its individual symptoms can be clearly or not so clearly manifested, and they can be observed temporarily or permanently.
Dynamic analysis of the clinical data depending on the exposure dose rate to critical organs is an important prerequisite for making the diagnosis of CRS. The changes observed in the bodily systems of an exposed individual should be followed up in dynamics, and CRS diagnosis implies both a due consideration of the initial data characterizing at least the status of the hematopoietic and nervous systems, before the exposure, and the results of the dynamic follow-up after the exposure.
The diagnosis of CRS should only be made by qualified experts with an in-depth knowledge of the clinical picture of CRS and an adequate experience in radiation medicine (Barabanova et al. 2007). The above-stated requirements are obligatory as the CRS diagnosis cannot be made based on the results of a single checkup by a general practitioner. Thus, the CRS diagnosis can only be made in retrospect on the basis of the results of a more or less prolonged medical supervision of the patient’s critical systems (hematopoietic, nervous, etc.) involving a comparison of the dynamics of the changes observed with the changes in the dose rate to the organ of interest, the mandatory analysis of the dose threshold, latency period, concomitant diseases, and non-radiation factors.
Taking into account the specific features of the physiology of the child’s organism, it is necessary to pay attention to the following features when examining children. The examinations of children with a low growth rate should include measurements of the content of growth hormone (GH). A deficit of GH can be revealed based on a weakened response of GH to pharmacological stimulants. In spite of the fact that a 24-h spontaneous GH secretion is the most sensitive method of evaluation, its applicability in clinical settings is rather low. Insulin resistance test is a generally accepted “gold standard” for GH deficiency evaluation in exposed patients (Lissett et al. 2001). Standard provocative tests may yield false-negative results, especially after a low dose of radiation exposure to the cranium, and should be interpreted with care. A reduced level of the GH-dependent markers, insulin-like growth factor (IGF-1), and IGF-binding protein 3 (IGFBP-3) is reliable though it lacks specificity for GH deficiency; however, it can provide additional information (Shalet et al. 1998).
When performing a screening for radiation-induced diseases of the thyroid gland, one should keep in mind that clinical examinations are of a limited value in terms of detecting nodular formations in the thyroid gland, while an ordinary ultrasound investigation can be a sensitive enough tool of screening, as nodular formations of the thyroid gland are found in 35–40 % of cases at autopsy or surgical intervention in the general population (Gleeson et al. 2002). The effectiveness of the radioisotope scanning is currently being evaluated. The individuals exposed to radiation in childhood are advised to undergo clinical examinations, including evaluation of the thyroid gland function, regularly for their whole life.
Following the identification of a hormone deficiency and taking into account the clinical indications, the patients are administered a hormone replacement therapy. Gonadotropin deficiency may be manifested by a range of symptoms from a subclinical biochemical insufficiency to a clinically observable hypogonadism. In cases of reduced concentration of sex hormones, the basal LH/FSH levels are usually normal (less frequently, lowered) with a decreased concentration of sex hormones, while GnRH demonstrated a delayed peak of gonadotropic reaction and/or a delayed decrease which were suggestive of a damage to the hypothalamus. A delayed reaction is indicative of damage to the hypophysis, whereas a mixed reaction can be interpreted as evidence for damage to the hypothalamus and the hypophysis. It is possible to differentiate between the primary and secondary pituitary insufficiency by means of repeated injection of GnRH (Yoshimoto et al. 1975).
7.1.2 Dose Threshold
The estimation of individual exposure doses is of special diagnostic value. Since CRS develops as a result of exposures at doses exceeding the dose threshold, the effect of doses below the threshold is regarded as unlikely, and any changes in the health status are not attributed to the radiation exposure. As it has been noted in Chap. 1, the dose threshold for CRS induction has not been accurately estimated as yet. Even the threshold dose values estimated for the workers of nuclear plants who received total-body external exposures to γ-radiation vary essentially within the range from 0.7 to 2–3 Gy, with dose rates varying from 0.1 to 1.0 Gy/year (Okladnikova 2001; Guskova et al. 2001, 2002; Barabanova et al. 2007; Osovets et al. 2011). Taking into account a rather high interindividual variability of radiosensitivity in humans, the dose threshold conducive to CRS development is represented by a rather wide range of doses. Thus, an important stage in diagnosing CRS is estimation of doses to organs with due consideration of RBE. The RBE dose dependence should be taken into consideration. At high doses, the RBE value is almost constant. However, the value of RBE increases with decreasing exposure dose (ICRP 2007).
However, not infrequently the estimation of individual organ doses under the conditions of chronic exposure presents a considerable difficulty; besides, it should be taken into account that even reconstructed doses harbor considerable uncertainties. As for the organ doses that have been estimated for exposed residents of the Techa River riverside villages and that should be used in the assessment of tissue reactions, they still involve significant uncertainties. The use of the new dosimetry system, TRDS-2009, has allowed individualization of dose estimates, especially estimates of the internal exposure doses based on individual whole-body counter measurements of 90Sr body contents for residents of the Techa riverside villages (Kozheurov 1994). It appears that the consistency of dose estimates is quite sufficient for the epidemiological analysis of radiation risk, but it is not sufficient for the verification of such deterministic effects as CRS. Thus, in fact, a doctor cannot always obtain the information on organ doses and is often compelled to use any dosimetric information allowing him to estimate, at least roughly, the order of doses.
In case the information on doses is unavailable, analysis of a specific clinical case would require the use of information on biological indicators of dose or radiation exposure, i.e., on specific changes detected mainly at molecular or cell levels which can enable dose reconstruction (e.g., the levels of chromosome aberrations (IAEA 1986) or micronuclei in blood lymphocytes (Müller and Streffer 1994)), or ascertainment of the fact of radiation exposure based, e.g., on the condition of the cutaneous covering (Hamilton et al. 1997). Other typical biological indicators of radiation exposure are as follows: blood cells, especially lymphocytes (Fliedner et al. 2007); comets (Müller 2007); γ-H2AX loci (Szumiel 2007); precocious chromosome condensation (Hatzi et al. 2006); and others. None of them is specific to radiation exposure. Radiation exposure biomarkers allow verification of the exposure received by an individual and in some cases a rough estimation of the individual exposure dose. In the absence of the data on doses based on physical dosimetry, doses can be reconstructed retrospectively, using the EPR analysis of tooth enamel or cytogenetic investigations, as late as years after the exposure. Thus, the FISH method based on the analysis of stable chromosome aberrations in blood lymphocytes allows reconstruction of individual doses which entail risk of CRS development even as late as many years after the exposure (Akleyev et al. 1995; Vozilova et al. 1998).
7.1.3 Dynamics of Exposure Dose Rates Registered in Critical Organs
Another factor that complicated considerably the CRS diagnosis in exposed residents of the Techa riverside villages was a considerable change in the exposure dose rate to critical organs, especially to the RBM, which was going on for a long time period. It should be noted that the dose rates, even to the BM, were low enough over many decades, whereas in the period of releases of radioactive waste, especially in 1951, it reached substantial values (Chap. 2). It is important to note that this pattern of dose rate dynamics is typical of accidental exposures of the general population who receive high dose rates during the accident and in the early postaccident period which is followed by a sharp decrease in the dose rates, and then, the population may be exposed to low doses over many years. The dynamics of the formation of CRS cases has shown that there is no clear-cut conformity with the mean values of the exposure dose rates to the RBM of the residents of the Techa riverside villages. In order to establish the CRS diagnosis, individual dose estimates and dose rate estimates are indispensable. The current estimates of the dose rates received by members of the Techa River communities represent just averaged annual doses and do not take into account the extreme nonuniformity of the waste releases. In view of the fact that the bulk portion of long-lived radionuclides was discharged in the first and second 10-day periods of October 1951, it can be expected that the residents of the nearby villages have been exposed at much higher dose rates in this period. In case CRS is suspected, it would be important to have in view the possibility that the annual threshold doses to individual organs could be exceeded in the period of the maximum radiation exposure. Therefore, the knowledge not only of the exposure dose values but also of the conditions of dose formation is required.
7.1.4 Latency Period
As it has been mentioned earlier, CRS is developing slowly over a certain time period after the onset of external exposure and radionuclide body intakes. The estimation of the duration of the latency period, which is determined by the exposure dose rate to the critical systems, is highly significant for making a correct diagnosis of CRS. The latency period of the CRS development is rather long which is influenced by the sufficient enough capacities of cells, tissues, and organ systems for recovery and compensation of the radiation damage to cells and tissues induced by a low dose rate exposure. As it has been noted above, the latency period of CRS depended on the exposure dose rate, so it varied over a wide range from 1 to 10 years in different persons. It is important, in case CRS is suspected, to keep in mind that identification of the latency period may depend on the diagnostic methods used, and the more sensitive the methods are, the earlier can the tissue reactions be revealed in case of chronic exposure. A too short period (less than a year) of the development of pathological changes after the onset of exposure and low exposure doses (below the threshold organ doses) would make the diagnosis look doubtful.
7.1.5 Individual Radiosensitivity
It is known that individuals differ considerably from each other in terms of radiosensitivity, and it is true not only in case of hereditary diseases. Many studies into the effects of chronic and fractionated exposure show a considerable variability of individual radiosensitivity which is determined by many factors (Crompton et al. 1997; Bentzen 2008; Torres-Roca and Stevens 2008). Individual radiosensitivity is determined by a contribution and an interaction of many factors of which the most important are reparation, regulation of cell cycle checkpoints, apoptosis, proliferation, migration and differentiation of cells, antioxidant and enzymatic status of cells, adaptive response, abscopal effect, genomic instability, hormonal and immune status, and genetic predisposition (ICRP 2007).
The genetic status of an individual exerts an essential influence on radiosensitivity. There are some genetic diseases, associated with immunodeficiency, and a high sensitivity to IR. Persons with ataxia-telangiectasia and similar disorders, Nijmegen breakage syndrome, heavy combined immunodeficiency, ligase IV syndrome, and Seckel syndrome have an extremely high radiosensitivity. A less marked increase in radiosensitivity is typical of patients with xeroderma pigmentosum, Fanconi anemia, progeria syndromes, and congenital dyskeratosis. Disorders of DNA reparation, disturbances in cell cycle regulation, and cell apoptosis control in such patients lead to high radiosensitivity. Some of them are associated with chromosome instability and an increased incidence of malignant neoplasms (UNSCEAR 2009). It should be noted, however, that such pathology occurs rather infrequently.
Other pathological conditions, such as autoimmune diseases and acquired immune deficiency syndrome (AIDS), also affecting the immune system, are associated with an increased radiosensitivity. A delay in the DNA damage reparation and an increased radiosensitivity of lymphocytes are manifested by patients with such autoimmune diseases as systemic lupus erythematosus, juvenile rheumatoid arthritis, systemic scleroderma, and polymyositis. The patients with aggravations of these diseases exhibit a marked increase in the radiosensitivity of lymphocytes compared to that manifested at a remission phase (Cossu et al. 1991).
Increased radiosensitivity noted in persons with AIDS results from the fact that IR activates replication of human immunodeficiency virus (HIV-1). It is assumed that the activation is mediated through the mechanism of abscopal effect with the participation of reactive oxygen species (ROS). Increased radiosensitivity in such persons can be related to lowered levels of endogenic antioxidants in their cells and to a chronic oxidative stress (UNSCEAR 2009).
There exists evidence that the type of the immune response to IR exposure is also genetically determined and associated with very highly polymorphic HLA genes (Konenkov and Trufakin 2002). Thus, it is important to note that genetic predisposition is only one of the factors determining the individual radiosensitivity. Unfortunately, it is difficult to take into account all (or very many of) the factors determining the specific features of radiosensitivity, but when diagnosing CRS it is essential to consider the initial health status, its objective characteristics (e.g., blood cell structure), and the accompanying diseases, including those associated with the increased radiosensitivity.
7.1.6 Analysis of Non-radiation Factors
The time factor complicates the CRS diagnosis not only because of a change in exposure doses with time but also due to the influence exerted by various non-radiation (“confounding”) factors during the latency period before the diagnosis of the syndrome is established. CRS diagnosis is also significantly complicated by other non-radiation environmental factors producing an adverse effect on the patients, as well as by the diseases with similar clinical manifestations (brucellosis, cerebral injuries, etc.), and factors of occupational hazards (toxicity of such chemical substances as arsenic and manganese compounds). Differential diagnosis between CRS and the above-indicated conditions is an obligatory component of the process of diagnosis verification (Sect. 7.2). The procedures of differential diagnosis should allow the physician to reject any possible diseases with similar clinical symptoms. It is important to point out that the existence of another cause (or causes) for the development of symptoms similar to CRS clinical picture does not rule out the effect of the radiation factor or a synergistic effect of these factors.
A typical example of problems a physician has to deal with is a combined effect of IR and non-radiation factors. Since the biological mechanisms responsible for inhibition of hematopoiesis and the CNS dysfunctions on account of CRS are not completely clear, there is no possibility to make the conclusion on whether there is an interaction between IR and non-radiation factors (chemical substances, infectious agents, etc.) and the way this interaction is proceeding (Sect. 7.2). It should be kept in mind that, as a rule, if combined, several diseases mutually influence each other, predominantly aggravating each other’s course. With the possibility of mutual potentiation, CRS symptoms can stand out distinctly against the background of a non-radiation pathology (e.g., in cases of blood diseases, cardiovascular system diseases, and infections). Under the conditions of an industrial nuclear facility, IR exposure can be combined with the effects of other factors (increased temperature and humidity, chemically harmful substances, e.g., acids, mercury, chlorine, lead, and organic solvents).
7.2 Differential Diagnosis of CRS
As it has been noted above, the clinical picture of CRS has no pathognomonic signs, hence, the necessity to make a differential diagnosis in each case when CRS is suspected. There is a need to make a differential diagnosis between CRS and a large number of somatic and infectious diseases, as well as the consequences of nervous system injuries and the effects of some adverse occupation-related factors. Although CRS symptoms are not specific, the symptom complex of the syndrome is characteristic of the certain period of its development, and the dynamics of occurrence of clinical signs clearly depends on the dose rate and its distribution in the body (Guskova and Baysogolov 1971).
Serious difficulties in terms of CRS diagnosis arise in cases of low and moderate degree of CRS involving functional changes in organs which vary over time and frequently lead to a misdiagnosis. Cases of CRS identified among residents of the Techa riverside villages who were mostly diagnosed with CRS of low severity serve as an illustrative result. CRS diagnosis was seriously complicated by lack of individual dosimetry data and insufficient information on the initial health status. A detailed clinical picture in cases of severe form of CRS cases, the availability of information on the initial health status, and the doses received allowed making a substantiated and accurate diagnosis. As it has been already noted above, a key to CRS diagnosis is a more or less prolonged follow-up of patients which allows assessment of the dynamics of changes taking place in the critical systems with a due consideration given to the organ doses (dose rates).
Although the combination of characteristic signs and the dynamics of CRS semiotics correlated with organ doses are typical of this syndrome, in some cases the diagnosis of the syndrome causes difficulties. Of special importance for making a differential diagnosis are the anamnestic data, particularly the information derived from the records contained in the person’s past history. As it has been pointed out above, it should be kept in mind that in real-life conditions (e.g., in occupational settings), the effect of IR can be combined with the effects of other adverse factors (increased temperature and humidity, chemically harmful substances: acids, mercury, chlorine, lead, organic solvents, etc.) which should also be taken into account (Kurshakov 1956).
Hematological semiotics is of special significance for the differential diagnosis of CRS. Taking into account that the most important hematological features of CRS include leukopenia, neutropenia, lymphopenia, and thrombocytopenia, a differential diagnosis is needed to exclude a large group of congenital and acquired conditions, characterized by similar changes in the blood. Considering the individual differences in leukocyte counts, it should be kept in mind that a variety of diseases, such as viral infections and some other (brucellosis, typhoid fever), are accompanied by a decrease in counts of leukocytes and neutrophils. The changes in the blood attributed to CRS have much in common with changes resulting from chronic poisoning with benzene, arsenic, and other industrial poisons. Thus, one of the main problems in the differential diagnosis of CRS is the ruling out exclusion of the non-radiation nature of cytopenia.
7.2.1 Leukopenia and Neutropenia
Leukopenia is known for the diversity of its etiology and pathogenesis; it is observed in many diseases and syndromes. Leukopenias can be subdivided into redistributive and true leukopenia. Redistributive leukopenia develops as a consequence of increased leukocyte migration into the tissues. It is encountered, for example, in cases of malaria and typhoid fever. True leukopenias reflect a decrease in the absolute count of white cells in the body as a result of the prevalence of loss of leukocyte death over regeneration. True leukopenia observed in cases of aplastic conditions (e.g., aplastic anemia) is associated with a decreased production of white cells by the aplastic BM (Vorobyev 1985).
Most often, leukopenia is mediated by a decline in the count of blood neutrophilic granulocytes. Neutropenia (neutrophil counts in peripheral blood less than 1.8·109/l) is conditioned by a temporary or permanent change in different pools of neutrophils and is diagnosed based on the results of several subsequent blood tests. If the absolute neutrophil count in blood exceeds 0.5·109/l, then, with normal neutrophil function, no substantial decrease in innate immunity occurs. Severe neutropenia (neutrophil count less than 0.2·109/l) is always associated with an increased risk of infectious complications, especially in cases where the decrease in neutrophil levels occurs rapidly. Constant chronic depletion of the neutrophilic reserve can occur without obvious clinical symptoms and manifest itself by a slight increase in temperature, stomatitis, lymphadenopathy, and recurrent pyoderma (Shiffman 2001).
Agranulocytosis is understood to be a profound neutropenia (less than 0.75·109/l), more often with the total leukocyte counts less than 1.0·109/l. Whatever the origin, in case of severe neutropenia, a reduced resistance to bacterial and fungal infection is marked. With more prolonged neutropenia, manifestations of pyoderma and superficial mycoses are possible.
Neutropenia may be selective, when the count of other blood cells is not reduced. Selective neutropenias may be either inherited or acquired. Neutropenia is often a manifestation of pancytopenia. Pancytopenia may be consequent on megaloblastic conditions, primary BM failure and secondary aplastic conditions observed in cases of onco-hematological damage to the BM, and hypersplenia.
The most common inherited forms of selective neutropenia are as follows:
Kostmann syndrome (infantile agranulocytosis) is associated with autosomal recessive mutation causing an insensitivity of promyelocytes to CSF effects. Patients are noted to have hyperplasia of BM granulocytic cell lineage and deficiency of myelocytes and more mature neutrophils. Persistently, low levels of neutrophils in blood are observed. Microcephaly, psychomotor retardation, and short stature may represent either a manifestation of a genetic defect or a consequence of severe pyogenic infections, occurring in these patients even in early childhood. Many patients die of sepsis in childhood. An increased risk of myeloid leukemia is observed in such patients.
Periodic (cyclic) neutropenia is an autosomal dominant disorder that is first observed in infancy and persists for decades. The clinical symptoms are typical of agranulocytosis. Neutropenia develops every 3–4 weeks, lasts for 3–6 days, and is accompanied by fever, mucositis, and skin infections. BM hypoplasia develops. The pathogenesis is considered to be associated with a reduced sensitivity of progenitor cells to the colony-stimulating factors.
Shwachman–Diamond–Oski syndrome is a combination of pancytopenia with exocrine pancreatic insufficiency. The pathogenesis involves autosomal recessive inheritance. Instead of pancytopenia, anemia and thrombocytopenia may occur. A characteristic symptom is steatorrhea. The signs of the syndrome often include short stature, mental retardation, metaphyseal dysostosis, and myocardial fibrosis. The outcome is as follows: 25 % of patients develop pancytopenia and 5 % leukemias.
Dyskeratosis congenita (Zinsser–Cole–Engman syndrome) is also a triad of reticulated hyperpigmentation on the face, neck, and shoulders, mucosal leukoplakia, and nail dystrophy. Types of inheritance: X-linked mode is predominant, and autosomal dominant and autosomal recessive modes are noted less frequently. In the second decade of life, about 50 % of patients develop neutropenia or aplastic anemia. Throughout life, there is an increased risk of developing squamous cell carcinoma or adenocarcinoma predominantly in the oropharynx and GIT. Correction of neutropenia may sometimes be achieved by androgen therapy in combination with prednisolone.
Chédiak–Higashi syndrome is characterized by inhibition of hematopoiesis, severe neutropenia, sometimes pancytopenia, lack of pigmentation of the skin and the iris (albinism), and progressive neurological disorders. Autosomal recessive type of inheritance is involved. The hallmark of this disease is the presence of giant cytoplasmic granules in leukocytes. Their formation is associated with abnormality of microtubular protein structure leading to disruption of polymerization of cytoskeleton microtubules of neutrophils, monocytes, and NK cells, which results in the disruption of phagosome–lysosome fusion, and a reduced mobility of granulocytes. Due to the deranged killer effect and migration of neutrophilic granulocytes, patients suffer from frequent and prolonged infections caused primarily by staphylococci, streptococci, and Pseudomonas aeruginosa.
Myeloid cachexia–neutropenia with tetraploid leukocytes is a syndrome which occurs in early childhood and is manifested by recurrent infections. Polyploid mature granulocytes are retained in the BM which entails a deficit of these cells in the blood. Various disorders of the neutrophil function are noted too. G-CSF therapy has shown a certain effect.
Reticular dysgenesis has shown a lesser interest in terms of the differential diagnosis of CRS. It is a hereditary, recessive, possibly X-linked disease, manifested by congenital granulocytosis, lymphopenia, and inhibition of cellular and humoral immunity. Infants develop infection in the first or second month of life. Clinically, the absence of the lymph nodes, tonsils, and thymus is detected; blood studies often reveal anemia and thrombocytopenia. There are no myeloid and lymphoid elements in the RBM; inhibition of the erythroid cell lineage may be observed. Sometimes, an emergency BM transplantation may be effective; otherwise, the patient’s life expectancy may be less than 4 months.
Benign autosomal Glassen neutropenia, inherited as a dominant trait, belongs to familial neutropenias. Inborn metabolism disorders, such as Gaucher disease, alter the architecture of the BM and are also able to contribute to neutropenia development. Neutropenia may also be registered in a number of congenital anemias characterized by pancytopenia (see Sect. 7.2.2).
Acquired neutropenia is substantially more common than the congenital type, and it can be caused by a variety of factors (infections, drugs, chemicals such as petrol, alcohol, and benzene and its homologues). Inhibition of BM hematopoiesis, followed by cytopenias, may occur in cases of acute leukemia, other hematological diseases, and multiple metastases of malignant tumors to bones. Acquired neutropenia (both isolated and pancytopenic) may be caused by the inhibition of neutrophil production, acceleration of neutrophil death, or a significant migration of neutrophils into tissues.
Most often neutropenia is noted in viral infections (infectious mononucleosis, viral hepatitis, HIV, rubella, infections caused by the Epstein–Barr virus, cytomegalovirus infection, yellow fever, chicken pox, the flu, and most of ARVI). Neutropenia is also characteristic of such bacterial infections as brucellosis, pertussis, salmonellosis, typhoid fever, rickettsiosis, relapsing fever, and some protozoiasis, e.g., leishmaniasis. Some bacterial infections (staphylococcal, tuberculosis, meningococcal) with a severe generalized course may lead to the development of secondary neutropenia after a long-term neutrophilic granulocytosis. In cases of a long-term infection, emaciation neutropenia may develop. This type of neutropenia is frequently observed in patients with infectious diseases who receive antineoplastic therapy or in those who have BM diseases and folic acid and/or vitamin B12 deficiency. In case of a purulent bacterial infection, neutropenia is a pejorative prognostic sign.
Presented below is a case of a differential diagnosis of CRS in a resident of the village of Muslyumovo whose neurological astheno-vegetative disorders and unstable decrease in blood neutrophil counts were observed in 1956. On examination at the URCRM clinic, the patient was diagnosed with infiltrative tuberculosis in the apex of the right lung. After a course of treatment for tuberculosis, no changes in the blood or neurological disorders were observed.
Patient D., born in 1935, was a resident in the village of Muslyumovo, Chelyabinsk Oblast. The village is located within 78 km of the site of releases of radioactive waste into the Techa River. The family’s wooden house, located within 20 m of the river, lacked modern conveniences. The family bathed in the river and used river water for all their domestic needs (drinking, cooking, washing clothes, cleaning floors, watering kitchen-gardens) and swam in the river. Calculated values of doses from external and internal exposure, estimated on the basis of dosimetry system TRDS-2009, were as follows: the dose to RBM at the time of the disease diagnosis amounted to 0.5 Gy, and the dose accumulated over the follow-up period was 0.73 Gy. The average annual RBM dose in 1951 (the period of maximum radiation exposures) was equal to 0.15 Gy/year.
Beginning in 1956, the patient was regularly seen at the clinical department of the URCRM. In 1956 she was diagnosed with CRS of low degree of severity. The diagnosis was based on the patient’s complaints of general weakness; easy fatigability at habitual levels of effort; malaise; lethargy; apathy; irritability; tearfulness; pain in the long, humeral, and tibial bones; muscular aches; dizziness at quick movements and bending head down; headache; daytime sleepiness; and restless night’s sleep. Nosebleeds started in May 1956. The findings of the neurological examination revealed a decrease in muscle tone, increased tendon reflexes in the upper and lower limbs, hand tremor, and hyperhidrosis. Dysmenorrhea, alopecia, and nail fragility were seen too. The diagnosis was also made taking into account the neurological syndromes (vegetative dysfunction and severe asthenia), changes in the peripheral blood (neutropenia with a left shift in the leukogram), and ovarian dysfunction (dysmenorrhea). The neutrophil blood counts showed a reduction to 1.3–1.6·109/l. BM examination was not conducted. X-ray examination detected lung tuberculosis at the stage of infiltration and induration. The diagnosis of CRS, based on the results of an examination conducted at the clinic of the Institute of Biophysics, the USSR Academy of Medical Sciences, was not confirmed.
After the treatment for tuberculosis, the patient’s cellular composition of the peripheral blood and hemoglobin level recovered and stayed within the normal range in the ensuing years. According to the results of the follow-up, the patient was diagnosed with the following diseases: cerebral atherosclerosis, chronic bronchitis, coronary heart disease, peptic ulcer, chronic gastritis, chronic pancreatitis, primary osteoarthrosis deformans, and osteochondrosis. In 1993, the patient developed a polyvalent allergy.
In March 1998, the patient developed skin vesicopustular rash, permanent skin itching, and sleep disorders. Polymorphic rash appeared quite suddenly, without any apparent cause, and covered the entire surface of the skin. Individual elements of the rash had a tendency toward fusion and a resultant formation of sores on the skin. In addition, there were changes in the GIT and the immune system, as well as certain ECG findings. There was a significant increase in pathogenic circulating immune complexes of medium size in the blood. A significant antigenic stimulation of B immunity was noted. The patient was examined, and her condition was thoroughly analyzed in the course of a teleconference conducted by the specialists in skin diseases of the University of Ulm clinic, Germany, and the URCRM specialists with the aim to confirm the diagnosis and develop a treatment strategy. As a result of the discussion, autoimmune neurodermatitis was diagnosed, and a treatment with tableted corticosteroids (prednisolone) was recommended. Following the administration of prednisolone at a daily dose of 0.5 g, the patient’s condition improved significantly. Her rash and itching stopped, and sleep and appetite improved. The dose of prednisolone was reduced to 20 mg/day with a gradual reduction of the dose (from March to October 1998, the dose was reduced from 20 to 5 mg/day) until the complete discontinuation of the drug.
As a result of the treatment, the elasticity of the skin completely recovered, and all the elements of the rash and itching disappeared. There remained irregular hyperpigmentation of the skin at the sites where the rash had been.
Clinical diagnosis: autoimmune neurodermatitis; polyvalent allergy; IHD, atherosclerotic cardiosclerosis with transient arrhythmias, circulation failure, sclerosis of the cerebral vessels and the aorta; duodenal ulcer in remission; chronic non-acute cholecystopancreatitis; chronic obstructive bronchitis, diffuse pneumofibrosis, pulmonary emphysema; primary deforming osteoarthrosis of joints of upper and lower limbs, 1st-degree joint functional failure; and widespread spinal osteochondrosis.
A special attention in the differential diagnosis of CRS in the residents of the Techa riverside villages was paid to brucellosis. Brucellosis is known as a zoonotic infectious disease with a clinical course similar to that of CRS, and in the period of radioactive contamination of the Techa River, it was widespread among the local population. Brucellosis is characterized by chronicity, and it mostly affects the locomotor system and hematopoiesis. The causative agents of the disease are Brucellas, which are transmitted to humans from animals (small and big cattle, pigs) via various routes. In the transfer to humans, meat and raw dairy products (milk, cheese, brinsen/feta cheese) are of epidemiological significance. Humans become infected through alimentary tract or direct contact. Most often, livestock breeders and workers employed by livestock production and processing enterprises become infected. Immune response in brucellosis is unstable and short-lived. Acute period is characterized by fever, chills, polyadenitis (especially cervical and axillary), toxico-septic manifestations in the respiratory system (bronchitis, pneumonia, bronchadenitis), and other manifestations of acute inflammation. Serous meningitis occurs very rarely, and its clinical picture develops slowly without obvious symptoms. In some patients, short-term arthralgias are observed, which disappear with a decline in the signs of intoxication. At later stages of the disease, there appear clinical signs of allergic reorganization of the organism.
Often the disease is characterized by a tendency toward a prolonged duration. The clinical picture is distinguished for polymorphism and lability of clinical symptoms, relapses, intoxication of mild severity, and prevalence of the focal damage to systems and organs. Relapses may occur in 1–2 months and later after the fading of the symptoms of acute brucellosis. Relapses of brucellosis occur with chills, fever, and sweating. Focal damages of individual organs and systems are observed, with the bone system being affected most commonly (Shuvalov et al. 2001).
Failures of the locomotor system are most frequently observed in the form of arthritis, periostitis, and perichondritis. Polyarthritis are typical with mainly the large joints (knee, hip, elbow, lumbosacral junction, etc.) involved in the pathological process; rarely the small joints are affected. Pains in muscles and joints and limitation of movements are observed. Swollen joints and hyperemia of the skin may occur due to periarthritis. Inflammatory changes may develop in the joints accompanied by the accumulation of exudate. In recurrent lesions of the joints, the intra-articular surfaces, menisci, and cartilages undergo changes, followed by articular cavity narrowing and dysfunction as a result of arthrosis, spondylarthrosis, and ankylosis. The occurrence of lesions of the sacroiliac joint in combination with ankylosis development is a characteristic feature. In chronic brucellosis, muscles are frequently affected. Myositis is accompanied by long-term pains of varying intensity. Apart from myositis, patients with brucellosis are often diagnosed with fibrositis.
Leukopenia, neutropenia, thrombocytopenia, eosinopenia, lymphocytosis, and monocytosis are noted in the peripheral blood.
Chronic intoxication can cause severe neuroses, reactive states, hypochondria, and psychosis. Short-term psychosensory disorders and optic–vestibular and receptor disorders are seen. Asthenic and hypochondriac syndromes are more persistent. As the vegetative nervous system becomes involved in the process, the vascular tone becomes impaired, and acrocyanosis, sweating, and trophic skin disorders occur. Disorders of the peripheral nervous system are manifested by radiculitises, plexitises, intercostal and other types of neuralgias, numbness, pareses, and cochlear and optic neuritises with a significant loss of hearing and visual acuity.
Patients develop endo-, peri-, and panvasculitis and increased capillary permeability. Myocarditis, endocarditis, and pancarditis are often seen. The liver and spleen are enlarged and indurated and their functions impaired. Urinary system is often affected which causes orchitis and epididymitis in men and oophoritis, salpingitis, endometriosis, menstrual disorders, and termination of pregnancy in women. In a number of cases, dysfunction of the thyroid gland, adrenal glands, and other endocrine organs is identified. Such patients lose working capacity for a long time period and may even become disabled.
Those who have had brucellosis often demonstrate certain residual effects, mostly of functional nature, which result from allergic rearrangements of the organism and disorders of the vegetative nervous system. Excessive sweating, irritability, changes in the neuropsychiatric sphere, and frequent arthralgia are noted in such persons. Pains in the joints are intermittent, without any visible changes in the joints. The body temperature is usually normal, sometimes low grade.
If brucellosis is suspected, the clinical data, epidemiological anamnesis, and the results of laboratory tests should be taken into consideration.
The epidemiological anamnesis indicative of a potential occupational or domestic infection is of great significance for establishing the diagnosis of brucellosis. The findings of laboratory investigations which serve as a basis for making a laboratory diagnosis of brucellosis involve bacteriological, biological, serological, and allergological methods of investigation. Isolation of Brucella from blood cultures provides a clear confirmation of the diagnosis. The causative agent may be obtained using specific media from blood, BM, bile, urine, lymph nodes, cerebrospinal fluid, articular fluid (in arthritis), vaginal discharge, and spleen punctate. In the laboratory practice of diagnosing brucellosis, the method of immunofluorescence allowing detection of Brucella in the biomaterial is used. One of the allergological methods of diagnosing brucellosis is Burnet reaction, based on the ability of the body sensitized by the brucellosis antigen to respond by developing a specific process in the form of redness and swelling in the skin. This reaction is of particular importance in the diagnosis of chronic brucellosis.
A case of differential diagnosis of chronic brucellosis in a patient with a suspicion of CRS is presented below.
Patient М., 1936, was a resident in the village of Metlino located within 7 km of the radioactive waste release site on the Techa River. The house stood within 200 m of the river bank. The family did not use river water for their household needs but often bathed in the river in summertime and caught fish in it. The dose of exposure to RBM (TRDS-2009) at the time of the diagnosis was equal to 1.69 Gy, and the annual average dose rate to the RBM in the period of maximum radiation exposure (1951) was 0.64 Gy. The patient’s dose to soft tissues in the year of CRS diagnosis amounted to 0.45 Gy and to 0.25 Gy in 1951.
In childhood the patient grew and developped normally. He started working at the age of 15, and worked as an agricultural laborer. From 1955 to 1958 the patient worked as a cattleman at a farm of cattle infected with brucellosis. From March 1961 moderate leukopenia (4–4.3·109/l) and neutropenia (1.5–1.8·109/l) were noted, with normal levels of erythrocytes, lymphocytes, and monocytes. There was no left shift in the leukogram. The patient complained of general fatigue, bone pains, and headaches. He noted bone pains and headaches to begin in 1955 but did not apply for medical advice and received no treatment. In addition, in 1960 the patient developed rapid fatigability after habitual work and poor appetite. Objective findings included static ataxia and intense dermographism. Based on complaints of asthenic character, leukopenia, and neutropenia, the diagnosis of mild CRS was suggested. The patient was examined regularly and received general health-improving therapy.
From 1966 onward, the patient noted pains in the limb joints and increased pains in the bones. Moderate leukopenia (4.0–4.9·109/l) persisted in the peripheral blood. An examination for brucellosis revealed a positive Burnet reaction. Taking into account the exposure to cattle infected with brucellosis and a positive Burnet reaction, the diagnosis of chronic locomotor form of brucellosis, in sub-compensation stage, was made. Occupational exposure to brucellosis-infected cattle was terminated; the patient was transferred to another job (truck driver).
Notwithstanding the therapy, the patient manifested bone pains and mild leukopenia (leukocyte count of 4–5.2·109/l) for a long time. Moderate blood neutropenia (1.8·109/l) was observed only once in 1976, while the counts of thrombocytes, erythrocytes, lymphocytes, and monocytes remained within the normal range of values throughout the follow-up period.
Autoimmune neutropenia in adults may be observed in patients with systemic immunopathological diseases with NOS autoantibodies, for example, in systemic lupus erythematosus, rheumatoid arthritis, Henoch–Schonlein disease, and Wegener granulomatosis. A specific symptom complex developing in the presence of pathogenic anti-neutrophil autoantibodies is Felty’s syndrome (neutropenia, splenomegaly, rheumatoid arthritis, and, sometimes, BM hypoplasia). Autoimmune neutropenia, as an isolated disorder, usually occurs in early childhood. The targets for autoantibodies are different neutrophil antigens (serologically referred to as NA1, NA2, NB1, ND1, ND2). The function of some of the antigens is unknown, while others have been identified (myeloperoxidase, lactoferrin, cytoskeletal proteins, components of chromatin, and others). In autoimmune neutropenia, mature neutrophils are affected, and their final maturation is disturbed; neutrophil phagocytosis is enhanced owing to mononuclear cells occurring in the tissues, spleen, and BM. Autoimmune neutropenia can reach the level of agranulocytosis in terms of deepness and degree of severity. A partial aplasia of the myeloid cell lineage can develop when there is thymoma or after its removal as a result of the impact exerted by autoantibodies and autoreactive lymphocytes on myeloid progenitor cells. Immunopathological etiology of agranulocytosis may be caused by the intake of drugs with the properties of haptens.
Drug-induced neutropenia develops due to the toxic damage of neutrophils at various stages of maturation; it is often identified in middle-aged and elderly people who have been taking certain drugs for long time periods. Neutropenia is most commonly associated with the use of peroxidase blockers – antithyroid drugs (Merkazolil). It is frequently enough caused by sulfasalazine, aminoglycoside, macrolide and β-lactam antibiotics, sulfonamides (Biseptol), procainamide hydrochloride, pyrazolones (amidopyrine) and other nonsteroidal anti-inflammatory drugs, phenothiazines (aminazin), and foxglove (Digitalis) drugs. The severity of damage in drug-induced neutropenia is often very high, reaching that seen in agranulocytosis, with the rapid development of the syndrome and high mortality. The mechanisms of drug-induced agranulocytosis are autoimmune or myelotoxic, like in case of aplastic anemia. In case of the autoimmune mechanism, the typical features are rapid development, lack of proportionality between the drug dose and the severity of neutropenia, provocation by small doses of drugs in patients undergoing the syndrome repeatedly, leukoagglutinating antibodies in blood, and idiosyncratic kind of reaction. Amidopyrine agranulocytosis is an example of immunopathological agranulocytosis. Myelotoxic neutropenia is characterized by slow development and absence of signs of immunological sensitization to the drug as a hapten. The effect of aminazin causing damage to isolated myeloid cells and the effect of cytostatic drugs provoking neutropenia as a part of pancytopenia are examples of myelotoxic agranulocytosis. Neutropenia observed in alcoholism is, to a certain extent, classified as toxic.
Alimentary toxic aleukia is a typical example of agranulocytosis and even pancytopenia induced by exogenous nondrug intoxication. This syndrome occurs as a result of poisoning with myelotoxic lysosomal toxins of mold origin. The most important role is played by sporofusarin lysosome destabilizer, a natural antibiotic of mold fungus Fusarium sporotrichiella, breeding in the overwintered grains (Pokrovsky and Krystev 1977). Significant concentrations of the toxin are attained in spring, during snowmelt. During the period of collectivization in the Soviet Union (1930–1934), there occurred epidemic outbreaks of toxic aleukia manifested by the symptoms of severe agranulocytosis, specific edematous necrotic angina, and, sometimes, thrombocytopenia and anemia. Pathogenesis of noma (alterative inflammation of the soft tissues of the mouth and face due to the exposure to saprophytic microflora, especially fusospirochetal symbiosis) is closely related to this type of agranulocytosis. The damage develops under the conditions of acquired immunodeficiency. Also, an important role of ergot, another grain fungus toxin (particularly, ergotoxine), in suppressing the immune system in noma, was suggested.
Clonal defects in granulocytes (e.g., in Marchiafava–Micheli disease) shorten their lifetime. In this case, the incursions of hemolytic anemia are accompanied by granulocytopenia. Neutropenia also occurs in certain metabolic disorders (ketoacidosis, glycogenosis, and tezaurismoze) due to which the lifetime of granulocytes is shortened and myelopoiesis, even with compensatory enhancement, is unable to maintain a sufficient pool of mature granulocytes. The deficiency of various essential food components (amino acids, vitamins, trace elements, etc.) due to starvation and especially kwashiorkor results in pancytopenia and agranulocytosis. Severe iron deficiency may be accompanied by mild neutropenia. Sometimes neutropenia manifests a complex etiology which involves alimentary, toxic (alcoholism, forced consumption of food containing mycotoxins), metabolic (ketoacidosis), and infectious origin.
Pseudoneutropenia develops due to increased margination of granulocytes. Such temporary decrease in the neutrophil count may be caused by hypersensitivity reactions, viremia, hemolysis, or hemodynamic changes.
As an example of complexity of the differential diagnosis of CRS, a clinical case of drug agranulocytosis development in a patient with hematopoiesis inhibition in CRS is given below. The patient’s agranulocytosis was distinguished by its chronic, recurrent, progressive course which entailed ankylosing osteoarthrosis of the hip joints and the spine, and, as a consequence, the patient developed disability at a young age, and in the ensuing years of her life agranulocytosis determined her health status.
Patient M. was born in 1941 in the village of Kurmanovo, located on the Techa River, within 89 km of the site of release of radioactive waste where she lived until resettlement in 1960. The family’s wooden house stood within 100 m from the river bank, it did not have any modern conveniences, and there was no well. The family used water from the river for all their domestic needs (drinking, cooking, livestock keeping, washing, cleaning the floor, etc.).
Beginning in 1955 on, the patient received regular follow-up examinations at the clinical department of the URCRM. Cumulative dose to RBM (TRDS-2009) was equal to 0.72 Gy, with the major contribution to the total dose made by the internal exposure (the external dose was only 0.03 Gy). Meanwhile, the dose to RBM at the time of CRS diagnosis was 0.5 Gy, including 0.03 Gy due to external γ-radiation. The average annual dose rate to RBM in 1951 (the period of the largest discharges into the river) amounted to 0.17 Gy.
In 1955, on account of the patient’s complaints of asthenic nature (weakness, fatigue, headaches, loss of appetite), ostealgic syndrome, and moderate neutropenia in the peripheral blood (up to 2.0·109/l), the patient was transferred to the Institute of Biophysics, the USSR Ministry of Health (Moscow), where she spent 5 months (December 1955–May 1956) undergoing in-depth examinations and receiving treatment. The examinations revealed endocrine insufficiency with manifest infantilism of sexual organs, symptoms of vegetative nervous system dysfunction (mild palpebral tremor, increased tendon and periosteal reflexes in the upper and lower limbs), and IV degree trachoma. During the course of symptomatic therapy, the patient’s condition deteriorated, the temperature rose to 39.5°, and acute lacunar angina accompanied by hepatomegaly developed. The peripheral blood leukocyte count decreased dramatically to 0.4·109/l, and agranulocytosis developed. BM preparations were indicative of acute agranulocytosis: scarcity of cellular elements, lack of granulocytes, a large number of disintegrated cells, and plasma cell hyperplasia. The patient received antibiotics, vitamins, blood and transfusion of packed leukocytes, etc. Twelve days later, while the patient was still on the prescribed therapeutic regimen, her condition improved: symptoms of angina disappeared, the temperature decreased, the count of leukocytes in peripheral blood increased to 1.5·109/l, and that of neutrophilic granulocytes increased up to 1.1·109/l. On May 8, 1956, the patient was operated on for acute appendicitis. The postoperative period was unremarkable. The patient was discharged from the clinic of the Institute of Biophysics, USSR Ministry of Health, with the diagnosis of CRS of medium degree of severity, with severe disorders of hematopoiesis, marked infantilism of sexual organs, endocrine disorders and vegetative dysfunction, trachoma, myopic astigmatism in both eyes, and post-appendectomy. During her stay in the hospital, her leukopenia and neutropenia persisted at 1.7–2.8·109
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Epidemiology of Chronic Radiation Syndrome
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