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1.  Lymphocyte Rich Hodgkin's Lymphoma Presented with Warm Hemolytic Anemia: A Case Report and Literature Review 
Case Reports in Hematology  2011;2011:385408.
Hodgkin's lymphoma accounts for ten percent of all lymphomas. In the United States, there are about 8000 new cases every year. This paper describes a case of lymphocyte-rich Hodgkin's lymphoma (LRHL) manifested by autoimmune hemolytic anemia (AIHA). A 27-year-old Israeli male presented with dizziness associated with one month of low-grade fevers and night sweats; he also complained of persistent cough, pruritus, and ten-pound weight lost during this time. The CBC revealed hemoglobin of 5.9 gm/dL, and direct Coomb's test detected multiple nonspecific antibodies consistent with the diagnosis of AIHA. Chest, abdomen, and pelvic CT scan showed mediastinal lymphadenopathy and splenomegaly. Lymph node biopsy revealed classic LRHL. AIHA resolved after completion of the first cycle of chemotherapy with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD); after six cycles, he went into complete remission. Although infrequent, AIHA can be responsible for the presenting symptoms of HL.
PMCID: PMC3420746  PMID: 22937306
2.  Reappraisal of the Etiology of Extracorpuscular Non-Autoimmune Acquired Hemolytic Anemia in 2657 Hospitalized Patients with Non-Neoplastic Disease 
Unlike autoimmune hemolytic anemia (AIHA), literature on the etiological study of non-autoimmune hemolytic anemia (non-AIHA) is scarce. The incidence and prevalence of non-AIHA in different geographic regions are largely unknown perhaps owing to the lack of perspective investigation and different profiles of etiologies from different geographic regions. We aimed to examine the real-world etiology or mechanisms of the non-hereditary non-AIHA from a nationwide population-based administrative claim database in Taiwan.
The National Health Insurance Research Database of Taiwan was adopted for this research. The studied population was total inpatient claim records including both pediatric and adult patients, contributed by a population of 23 million insured individuals in Taiwan. From 2002 to 2008, we retrieved 3,903 patients having no pre-existing malignancy discharged after inpatient management for acquired hemolytic anemia, which was defined as coding in discharge diagnoses containing ICD-9-CM code 283. By contrast, ICD-9-CM code 282 and all of the sub-codes are for hereditary hemolytic anemias.
AIHA accounted for 32% of the total cases. Among 2,657 patients with non-AIHA, mechanical or microangiopathic mechanism accounted for 19% of cases; hemolytic-uremic syndrome (HUS) 4%, hemoglobinuria because of hemolysis from external causes such as paroxysmal nocturnal hemoglobinuria (PNH) and march hemoglobinuria 7%, and chronic idiopathic hemolytic anemia or other unspecified non-AIHA 69%. We looked further for specific etiology or mechanism for this group of patients with non-hereditary extrinsic non-AIHA (n = 2,657). The explanatory disease states or conditions were splenomegaly; alcohol use disorder (spur cell hemolysis); heart-valve prosthesis; malignant hypertension; disseminated intravascular coagulation; transfusion reaction; dengue fever-induced hemolytic anemia; direct parasitization; snake, lizard, or spider bite; and Wilson’s disease with internal toxin mechanism. All these cases can explain up to 34.6% of all the non-hereditary extrinsic non-AIHA cases. Fragmentation hemolysis (HUS, heart-valve prosthesis, malignant hypertension, and disseminated intravascular coagulation) accounted for 7.4% of non-AIHA hospitalized patients with non-neoplastic disease.
This article is the first one to clearly demonstrate that the non-neoplastic-induced HUS requiring hospitalization cases in Taiwan, which has a population of over 23 million were 110 over a span of seven years, 16 cases per year. Although the etiologies of non-AIHA are well known and described in the literature, this work added the statistical percentages of the various etiologies of non-AIHA in Taiwan.
PMCID: PMC3999811  PMID: 24808725
non-immune hemolytic anemia; anemia; hemolytic; etiology; causality; extracorpuscular; hospitalized; NHIRD
3.  A Case of Non-Hodgkin's Lymphoma in Patient with Coombs' Negative Hemolytic Anemia and Idiopathic Thrombocytopenic Purpura 
Coombs' negative autoimmune hemolytic anemia (AIHA) is a rare disease which shares similar clinical and hematological features with Coombs' positive AIHA, but its exact frequency remains unknown. There have been few reports of idiopathic thrombocytopenic purpura (ITP) and Coombs' negative AIHA associated with other lymphoproliferative disorders (LPDs). Since there is a well known association between LPDs and autoimmune phenomena, it is important to investigate the possibility of an underlying malignancy. We report a case of ITP and Coombs' negative AIHA associated with diffuse large B-cell lymphoma.
PMCID: PMC3322204  PMID: 22500164
Lymphoma; Hemolytic anemia; Coombs' test; Idiopathic thrombocytopenic purpura
4.  Autoimmune hemolytic anemia in a patient with Malaria 
Autoimmune Hemolytic Anemia (AIHA), a very infrequent condition which represents a group of disorders in which presence of autoantibodies directed against self-antigens leads to shortened red cell survival. Till date, a very few cases of AIHA in Malaria patients are reported worldwide but still AIHA should be considered a relatively rare cause of anemia in malaria. A 20 year male presented with intermittent fever since seven days and yellowish discoloration of urine and sclera since 5 days. He was transfused three units of blood at a private clinic before one month. On examination, pallor, icterus and spelnomegaly were present. Hemoglobin (Hb) was 3.2 gm% and peripheral smear revealed ring forms of both Plasmodium vivax and Plasmodium falciparum. Serum LDH and Serum billirubin (Indirect and Direct) were high. This patient’s blood group was B +ve with positive autocontrol. Indirect Antiglobulin Test (IAT), antibody screening and antibody identification were pan-positive with reaction strength of +4 against each cell. Direct Antiglobulin Test was +4 positive anti IgG and negative with anti C3. He was treated with Artesunate and methylprednisone. Least incompatible, saline washed O Neg and B neg red cells were transfused on the 2nd day of starting treatment. Hb was raised to 6.1 gm% on 4th day. Patient was discharged on 9th day with Hb 7.0 gm% with oral tapering dose of steroids. In the above case, patient was suffering from high grade malarial parasitemia with co-existing autoimmune RBC destruction by IgG auto-antibodies which led to sudden drop in Hb and rise in serum LDH and indirect billirubin. Least incompatible packed red cells along with antimalarials and steroids led to clinical improvement. So far, one case report each from India, Korea, Canada and Germany and one case series report of three cases from India have been reported. Under-reporting or rarity of this phenomenon may be accountable for this.
PMCID: PMC3757778  PMID: 24014948
Autoimmune Hemolytic Anemia; autoantibodies; malaria
1. Minute beta hemolytic streptococci were found to occur from one-third to one-half as frequently in normal individuals as do ordinary beta hemolytic streptococci. 2. They were rarely isolated from the rhinopharynges of individuals suffering from chronic disease. 3. In acute respiratory tract infection other than that due to the ordinary beta hemolytic streptococcus the incidence of minute streptococci was slightly higher than in normal individuals. 4. In acute streptococcal infections, scarlet fever and acute tonsillitis, for example, the incidence of minute hemolytic streptococci did not significantly vary from the incidence found in normal human beings. 5. Minute beta hemolytic streptococci were found in the throats of 33 out of 42 patients ill with glomerular nephritis and in 25 out of 59 patients who were suffering from the various manifestations of rheumatic fever. 6. In glomerular nephritis and rheumatic infection the minute beta hemolytic streptococci were isolated from the throats of more patients than were the ordinary beta hemolytic streptococci.
PMCID: PMC2132431  PMID: 19870327
6.  Acute Q fever in Portugal. Epidemiological and clinical features of 32 hospitalized patients 
Germs  2012;2(2):43-59.
Q fever is a worldwide zoonosis caused by Coxiella burnetii. The main characteristic of acute Q fever is its clinical polymorphism, usually presenting as a febrile illness with varying degrees of hepatitis and/or pneumonia. Q fever is endemic in Portugal, and it is an obligatory notifiable disease since 1999. However, its epidemiological and clinical characteristics are still incompletely described.
We performed a retrospective study of 32 cases admitted in the Infectious Diseases Department, Santa Maria’s University Hospital, from January 2001 to December 2010, in whom acute Q fever was diagnosed by the presence of antibodies to phase II Coxiella burnetii antigens associated with a compatible clinical syndrome.
Out of the 32 cases recorded, 29 (91%) were male, with a male:female ratio of 9.7:1. Individuals at productive age were mainly affected (88%, n=28, with ages between 25 and 64 years). Clinically, the most common manifestation of acute Q fever was hepatic involvement (84%, n=27), which occurred isolated in 53% (n=17) of the cases. Hepatitis was more severe, presenting with higher values of liver function tests, in patients presenting both pulmonary and hepatic involvement. Additionally, we report one case of myocarditis and another one with neurological involvement. Empiric but appropriate antibiotic therapy was given in 66% (n=21) of the cases. There was a complete recovery in 94% (n=30) of the patients, and one death. We confirmed the sub-notification of this disease in Portugal, with only 47% (n=15) of the cases notified.
In Portugal further studies are needed to confirm our results. From the 32 cases studied, acute Q fever presented more frequently as a febrile disease with hepatic involvement affecting mainly young male individuals. Furthermore, acute Q fever is clearly underdiagnosed and underreported in Portugal, which suggests that an increased awareness of the disease is needed, together with a broader use of serological testing.
PMCID: PMC3882866  PMID: 24432263
Coxiella burnetii; acute Q fever; epidemiology; hepatitis; cholestasis; pneumonia; Portugal
Certain factors of climate are favorable to streptococcus respiratory diseases. In those tropical environments where hemolytic streptococcus is unusual in the throat flora, scarlet fever is unknown and rheumatic fever rare. In New York City, however, following epidemic waves of pharyngitis with hemolytic streptococcus the incidence of rheumatic fever rises precipitously. The correlation between the geographical distribution of hemolytic streptococcus and rheumatic fever is a definite one. Furthermore, in New York City during the seasons of the year in which hemolytic streptococcus is seldom recovered from the pharynx, acute attacks of rheumatism are unusual. Corresponding to the seasonal rise in hemolytic streptococcus infections, the curve of incidence of acute rheumatism shows a similar form. Among the children of wealthy patients, enjoying great protection, hemolytic streptococcus has been recovered infrequently from the throat, and rheumatism has not been encountered during this study. Among the poor under observation in New York City, however, the organism is found frequently in the pharyngeal flora, and rheumatic fever is common. The findings suggest that poverty and unhygienic living conditions favor both the activity of hemolytic streptococcus in the throat and the incidence of rheumatic fever. Moreover, localized outbreaks of rheumatism have been observed frequently following epidemics of "sore throat". Bacteriological studies of these upper respiratory infections demonstrate a close relationship between the advent of hemolytic streptococcus in the throat flora and the outbreak of rheumatic fever in susceptible individuals. In addition to these studies of streptococcus infections and their relationship to the development of rheumatic fever, observations of the rheumatic patient add further emphasis to this association. First, among a group of rheumatic children in an isolated environment, reactivation of the rheumatic process has been recognized only following the advent of hemolytic streptococcus in the throat flora. Also, an investigation of families in which several members have rheumatic heart disease has led to the same conclusion. Recrudescences of the disease have been observed under a variety of conditions among these individuals. However, the one constant factor in the outbreaks of recrudescences in rheumatic homes is their association with family epidemics of hemolytic streptococcus infection. Moreover, by studying rheumatic patients before, during and after transplantation to a tropical environment, it has been possible to demonstrate a close relationship between activity of the disease process and infection with hemolytic streptococcus. While the rheumatic patients remained in the tropics this organism was not recovered from the pharyngeal flora, and the disease process seemed quiescent. On return to New York City, those individuals who have escaped respiratory infection have remained symptom-free. However, of those who have contracted hemolytic streptococcus pharyngitis, each has developed a rheumatic attack within 3 weeks after infection. Finally, extensive bacteriological studies made in ambulatory rheumatic subjects over a period of 4 years have demonstrated that the individuals who escape respiratory disease remain free of rheumatic manifestations. On the other hand, the majority of rheumatic patients who contract hemolytic streptococcus pharyngitis experience shortly afterward a definite recrudescence of their disease. In conclusion, there is a close relationship between respiratory infection with hemolytic streptococcus and activity of the rheumatic process in susceptible individuals.
PMCID: PMC2132196  PMID: 19870089
8.  Giant cell hepatitis with autoimmune hemolytic anemia in a nine month old infant 
World Journal of Hepatology  2013;5(4):226-229.
Giant cell hepatitis (GCH) with autoimmune hemolytic anemia is a rare entity, limited to young children, with an unknown pathogenesis. We report the case of 9-mo old who presented with fever, diarrhea and jaundice four days before hospitalization. Physical examination found pallor, jaundice and hepatosplenomegaly. The laboratory workup showed serum total bilirubin at 101 μmol/L, conjugated bilirubin at 84 μmol/L, hemolytic anemia, thrombocytopenia and immunoglobulin G (IgG) and anti-C3d positive direct Coombs’ test. The antinuclear, anti-smooth muscle and liver kidney microsomes 1 non-organ specific autoantibodies, antiendomisium antibodies were negative. Serological assays for viral hepatitis B and C, cytomegalovirus, herpes simplex and Epstein Barr virus were negative. The association of acute liver failure, Evan’s syndrome, positive direct Coomb’s test of mixed type (IgG and C3) and the absence of organ and non-organ specific autoantibodies suggested the diagnosis of GCH. The diagnosis was confirmed by a needle liver biopsy. The patient was treated by corticosteroids, immunomodulatory therapy and azathioprine but died with septicemia.
PMCID: PMC3648655  PMID: 23671728
Giant cell hepatitis; Anemia; Hemolytic; Autoimmune; Child
9.  Hypercalcemia after transplant nephrectomy in a hemodialysis patient: a case report 
Hypercalcemia is a complication often seen in chronic hemodialysis patients. A rare cause of this condition is sarcoidosis. Its highly variable clinical presentation is challenging. Especially in patients suffering chronic kidney graft failure the nonspecific constitutional symptoms of sarcoidosis like fever, weight loss, arthralgia and fatigue may be easily misleading.
Case presentation
A 51 year old male developed hypercalcemia, arthralgia and B-symptoms after explantation of his kidney graft because of suspected acute rejection. The removed kidney showed vasculopathy and tubulointerstitial nephritis, which had not been overt in the biopsy taken half a year earlier. Despite explantation and withdrawal of the immunosuppression the patient's general condition deteriorated progressively. A rapid rise in serum calcium finally provoked us to check for sarcoidosis. CT scans of the lungs, broncho-alveolar-lavage and further lab tests confirmed the diagnosis.
This case demonstrates that withdrawal of immunosuppressive drugs sometimes unmasks sarcoidosis. It should be considered as differential diagnosis even in hemodialysis patients, in whom other reasons for hypercalcemia are much more common.
PMCID: PMC2241629  PMID: 18053167
10.  Q Fever, Spotted Fever Group, and Typhus Group Rickettsioses Among Hospitalized Febrile Patients in Northern Tanzania 
In a prospective cohort study of febrile patients in northern Tanzania, Q fever and spotted fever group rickettsiosis were common but were not diagnosed by physicians in the absence of specific clinical features and local diagnostic methods.
Background. The importance of Q fever, spotted fever group rickettsiosis (SFGR), and typhus group rickettsiosis (TGR) as causes of febrile illness in sub-Saharan Africa is unknown; the putative role of Q fever as a human immunodeficiency virus (HIV) coinfection is unclear.
Methods. We identified febrile inpatients in Moshi, Tanzania, from September 2007 through August 2008 and collected acute- and convalescent-phase serum samples. A ≥4-fold increase in immunoglobulin (Ig) G immunfluorescence assay (IFA) titer to Coxiella burnetii phase II antigen defined acute Q fever. A ≥4-fold increase in IgG IFA titer to Rickettsia conorii or Rickettsia typhi antigen defined SFGR and TGR, respectively.
Results. Among 870 patients, 483 (55.5%) were tested for acute Q fever, and 450 (51.7%) were tested for acute SFGR and TGR. Results suggested acute Q fever in 24 (5.0%) patients and SFGR and TGR in 36 (8.0%) and 2 (0.5%) patients, respectively. Acute Q fever was associated with hepato- or splenomegaly (odds ratio [OR], 3.1; P = .028), anemia (OR, 3.0; P = .009), leukopenia (OR, 3.9; P = .013), jaundice (OR, 7.1; P = .007), and onset during the dry season (OR, 2.7; P = .021). HIV infection was not associated with acute Q fever (OR, 1.7; P = .231). Acute SFGR was associated with leukopenia (OR, 4.1; P = .003) and with evidence of other zoonoses (OR, 2.2; P = .045).
Conclusions. Despite being common causes of febrile illness in northern Tanzania, Q fever and SFGR are not diagnosed or managed with targeted antimicrobials. C. burnetii does not appear to be an HIV-associated co-infection.
PMCID: PMC3148261  PMID: 21810740
11.  Graves' Disease Causing Pancytopenia and Autoimmune Hemolytic Anemia at Different Time Intervals: A Case Report and a Review of the Literature 
Case Reports in Medicine  2013;2013:194542.
Graves' disease (GD) is associated with various hematologic abnormalities but pancytopenia and autoimmune hemolytic anemia (AIHA) are reported very rarely. Herein, we report a patient with GD who had both of these rare complications at different time intervals, along with a review of the related literature. The patient was a 70-year-old man who, during a hospitalization, was also noted to have pancytopenia and elevated thyroid hormone levels. Complete hematologic workup was unremarkable and his pancytopenia was attributed to hyperthyroidism. He was started on methimazole but unfortunately did not return for followup and stopped methimazole after a few weeks. A year later, he presented with fatigue and weight loss. Labs showed hyperthyroidism and isolated anemia (hemoglobin 7 g/dL). He had positive direct Coombs test and elevated reticulocyte index. He was diagnosed with AIHA and started on glucocorticoids. GD was confirmed with elevated levels of thyroid stimulating immunoglobulins and thyroid uptake and scan. He was treated with methimazole and radioactive iodine ablation. His hemoglobin improved to 10.7 g/dL at discharge without blood transfusion. Graves' disease should be considered in the differential diagnosis of hematologic abnormalities. These abnormalities in the setting of GD generally respond well to antithyroid treatment.
PMCID: PMC3844236  PMID: 24319463
12.  Q Fever myocarditis 
Hippokratia  2008;12(1):46-49.
Clinical manifestations of Q fever infection are fever, productive cough, decrease in exercise tolerance and chills. Cardiovascular involvement is well recognized and usually presents as endocarditis and infection of an aneurysm or vascular graft. Myocarditis has only rarely been described as a manifestation of acute Q fever infection. In this report we describe a case of a young adult who presented with angina-like symptoms and ECG and biochemical markers indicative of acute coronary syndrome. The diagnosis of myocarditis was ultimately made based on the results of a normal coronary angiography and increased anti-Coxiella burnetii antibody titer. The patient has not developed dilated cardiomyopathy after two years of follow up.
PMCID: PMC2532961  PMID: 18923753
Coxiella burnetii; Q fever; myocarditis; antibody titer
13.  Autoimmune Complications after Hematopoietic Stem Cell Transplantation in Children with Nonmalignant Disorders 
The Scientific World Journal  2014;2014:581657.
Background. Hematopoietic stem cell transplantation (HSCT) remains the only curative treatment for many nonmalignant disorders, such as autoimmune disorders, inborn metabolic disorders, hemoglobinopathies, and immunodeficiency disorders. Autoimmune complications (AICs) after HSCT, such as autoimmune cytopenias, autoimmune hepatitis, primary biliary cirrhosis, and autoimmune cutaneous manifestations, are still neither well defined nor characterized. Patients. Between 2000 and 2012, 92 patients (47 males, 45 females) were treated with HSCT in our hospital, 51 with congenital hemoglobinopathies, 19 with primary immunodeficiency disease, 10 with metabolic disorders, five with Fanconi anemia, three with aplastic anemia, and four with familial hemophagocytic lymphohistiocytosis. Results. Mean age at HSCT was 6.4 years (range, 0.2–32 years) and mean duration of followup after HSCT was 6.81 years (range, 1–11 years). Sixteen (17.4%) patients developed chronic GVHD and five (5.4%) showed sclerodermatous features. Five (5.4%) patients were diagnosed with scleroderma manifestations, six (6.5%) with vitiligo, six (6.5%) with autoimmune hemolytic anemia (AIHA), six (6.5%) with idiopathic thrombocytopenia, three (3.3%) with mild leucopenia, two (2.2%) with aplastic anemia, two (2.2%) (one boy, one girl) with autoimmune thyroid disease, and one (1.1%) with autoimmune hepatitis. Conclusions. It was concluded that AICs are clinically significant complications after HSCT that contribute to morbidity but not to mortality. AICs are more frequent after HSCT for metabolic disorders, and sclerodermatous GVHD is more significant in children who underwent allogeneic HSCT for hemoglobinopathies. The potential to identify risk factors for AICs could lead to less morbidity and mortality and to maintain the patient's quality of life.
PMCID: PMC3916029  PMID: 24574898
14.  Autoimmune Cytopenias in Chronic Lymphocytic Leukemia, Facts and Myths 
CLL has been defined as presence of more than 5000 small mature appearing monoclonal B lymphocytes with a specific immunophenotype in peripheral blood. It is a well-known fact that CLL is associated with autoimmune cytopenias. CLL cells are CD5+ B lymphocytes, and usually are not the “guilty” cells which produce autoantibodies. T cell defect is another characteristic of CLL and the total number of T cells is increased, and there is inversion of the CD4/CD8 ratio. Autoimmune hemolytic anemia (AIHA) is the most common autoimmune complication of CLL and has been reported in 10–25% of CLL patients. However, the stage-adjusted estimated rate of AIHA in CLL is about 5%. Conversely, CLL is three times more common in patients who present with AIHA. Direct agglutinin test (DAT) is positive in 7–14% of CLL patients but AIHA may also occur in DAT negative patients.
Autoimmune thrombocytopenia (AIT) is the second most common complication of CLL and has been reported in 2–3% of patients. DAT is positive in AIT but presence of antiplatelet antibodies is neither diagnostic nor reliable. Autoimmune neutropenia (AIN) and pure red cell aplasia (PRCA) are very rare complications of CLL and like other autoimmune complications of CLL may occur at any clinical stage. It is believed that most case reports of AIN and PRCA in CLL actually belong to large granular lymphocytic leukemia (LGL). Non-hematologic autoimmune complications of CLL including cold agglutinin disease (CAD), paraneoplastic pemphigus (PNP), acquired angioedema, and anti-myelin associated globulin are rare.
Before starting any treatment, clinicians should distinguish between autoimmune cytopenias and massive bone marrow infiltration since autoimmune complications of CLL are not necessarily equal to advanced disease with poor prognosis. According to IWCLL guideline, steroids are the mainstay of treatment of simple autoimmunity. Intravenous immunoglobulin (IVIg), cyclosporine, and rituximab are used in complex, steroid refractory cases. Monotherapy with purine analogues and alkylating agents should be avoided as they may increase CLL associated autoimmune complications.
PMCID: PMC3867225  PMID: 24363883
15.  Paroxysmal nocturnal hemoglobinuria in systemic lupus erythematosus: a case report 
Paroxysmal nocturnal hemoglobinuria is an acquired disorder of hemopoiesis and is characterized by recurrent episodes of intravascular hemolysis due to an increased sensitivity to complement-mediated hemolysis. Systemic lupus erythematosus with paroxysmal nocturnal hemoglobinuria is very rare. We report a case of paroxysmal nocturnal hemoglobinuria that developed in a patient with systemic lupus erythematosus and lupus nephritis.
Case presentation
A 29-year-old Mongolian woman had systemic lupus erythematosus, which manifested only as skin lesions when she was 12 years old. She had leg edema and proteinuria when she was 23 years old, and a renal biopsy revealed lupus nephritis (World Health Organization type IV). She had been treated with steroids and immunosuppressant therapy. At 29, she had headaches, nausea, general fatigue, and severe pancytopenia and was admitted to our hospital. A laboratory evaluation showed hemolytic anemia. Further examination showed a neutrophil alkaline phosphatase score of 46 points, a CD55 value of 18%, and a CD59 value of 78.6%. The results of Ham test and sugar water tests were positive. The constellation of symptoms throughout the clinical course and the laboratory findings suggested paroxysmal nocturnal hemoglobinuria.
To the best of our knowledge, systemic lupus erythematosus with paroxysmal nocturnal hemoglobinuria is very rare. Clinicians should be aware of the association between autoimmune and hematological diseases.
PMCID: PMC3262772  PMID: 22081908
16.  Q Fever 
Clinical Microbiology Reviews  1999;12(4):518-553.
Q fever is a zoonosis with a worldwide distribution with the exception of New Zealand. The disease is caused by Coxiella burnetii, a strictly intracellular, gram-negative bacterium. Many species of mammals, birds, and ticks are reservoirs of C. burnetii in nature. C. burnetii infection is most often latent in animals, with persistent shedding of bacteria into the environment. However, in females intermittent high-level shedding occurs at the time of parturition, with millions of bacteria being released per gram of placenta. Humans are usually infected by contaminated aerosols from domestic animals, particularly after contact with parturient females and their birth products. Although often asymptomatic, Q fever may manifest in humans as an acute disease (mainly as a self-limited febrile illness, pneumonia, or hepatitis) or as a chronic disease (mainly endocarditis), especially in patients with previous valvulopathy and to a lesser extent in immunocompromised hosts and in pregnant women. Specific diagnosis of Q fever remains based upon serology. Immunoglobulin M (IgM) and IgG antiphase II antibodies are detected 2 to 3 weeks after infection with C. burnetii, whereas the presence of IgG antiphase I C. burnetii antibodies at titers of ≥1:800 by microimmunofluorescence is indicative of chronic Q fever. The tetracyclines are still considered the mainstay of antibiotic therapy of acute Q fever, whereas antibiotic combinations administered over prolonged periods are necessary to prevent relapses in Q fever endocarditis patients. Although the protective role of Q fever vaccination with whole-cell extracts has been established, the population which should be primarily vaccinated remains to be clearly identified. Vaccination should probably be considered in the population at high risk for Q fever endocarditis.
PMCID: PMC88923  PMID: 10515901
The similarity in the cases of rat-bite fever recorded in the literature establishes it as a definite clinical entity. The same symptomatology occurs in cases from Asia, Europe, and America. The greater frequency of the disease in Japan than elsewhere is probably due to the housing conditions and habits of the people resulting in the more frequent occurrence of rat-bites. It does not seem necessary to consider that cases occurring in Europe and America are due to the bites of rats that have been imported from Japan. The clinical picture and course of the disease indicate that it is infectious in origin. Until Schottmüller's case appeared in 1914, the etiology had been undiscovered. He isolated from his case in eight consecutive blood cultures a streptothrix which he has designated Streptothrix muris ratti. His work has been confirmed by the isolation of an identical streptothrix from the blood during life and at autopsy in the case here reported. Further confirmation of the etiological relationship of this organism to the infection in our patient is found in the production of powerful agglutinins for the organism in the blood serum of this case and in the demonstration of the organism in the vegetation on the mitral valve. It is not unreasonable to suppose that Proescher (13) observed the same organism in the sections of the excised wound in his case. Although it is fully realized that Koch's postulates have not been fulfilled in the absence of successful animal experimentation, nevertheless the accumulated evidence here presented leaves little reason to doubt that the specific cause of rat-bite fever is Streptothrix muris ratti. The pathology of rat-bite fever has hitherto been largely a matter of surmise. One autopsy only has been recorded in the literature (Miura (22)), and nothing abnormal was noted other than injection of the pial vessels. The autopsy in the case here reported has proved of considerable interest in the extent and character of the lesions found. A streptothrix septicemia with the localization of the organism in the mitral valve producing an acute ulcerative endocarditis is the most striking feature of the case. The infarcts of the spleen and kidney are a natural sequence of the endocarditis. The subacute lesions of the myocardium, liver, adrenal, and kidneys, glomerular and interstitial, are all of a similar nature, consisting of areas infiltrated with leukocytes, lymphocytes, plasma, and endothelial cells with varying degrees of degeneration of the normal cells of the affected area. In no instance has the presence of the streptothrix in these lesions been demonstrated, and it is not unreasonable to assume that they are toxic in origin. The data here presented may be correlated with the clinical features of rat-bite fever to give us a clear understanding of the course and nature of the disease. The patient is inoculated by the bite of a rat with Streptothrix muris ratti. After a variable incubation period a non-suppurative inflammatory reaction occurs at the site of the wound with extension to the neighboring lymphatics and lymph nodes. Invasion of the blood stream follows, accompanied by the onset of severe toxic symptoms. Clinically the nervous system and frequently the kidneys seem to be especially involved. That the myocardium, liver, and adrenals may also suffer is shown by the autopsy findings in the case reported above. Ulcerative endocarditis is probably a rare occurrence. In the majority of cases after a more or less prolonged course, the disease terminates spontaneously and so may be considered a self-limited infection. This is presumably brought about by the development in the body of a protective mechanism against the streptothrix. That such a process does occur is evidenced by the demonstration of agglutinins in our case. Whether a permanent immunity is acquired after one attack of rat-bite fever is not known. No instances of a second infection are recorded in the literature. Although rat-bite fever varies somewhat in its symptomatology in individual cases, the picture is sufficiently characteristic to make the diagnosis not a difficult matter. The history of a rat-bite, latent incubation period with subsequent non-suppurative inflammatory reaction of the wound, lymphangitis, and enlarged lymph nodes, severe chill at onset, high fever of the relapsing type, intense muscular pain and nervous symptoms, and the characteristic bluish red exanthem, present a symptom-complex not easily overlooked. The disease is frequently complicated by a severe nephritis, and prolonged cases develop a high grade of anemia and cachexia. In the case here reported ulcerative endocarditis occurred. In the large majority of cases the prognosis is favorable for a successful termination. The patients, however, are often incapacitated for a considerable period of time The mortality is about 10 per cent, death usually occurring in the first febrile period apparently from a profound toxemia, or at a later stage due to the development of a severe nephritis. Until recently treatment has been entirely symptomatic and has been of little avail in altering the course of the disease. Miyake has found immediate treatment of the wound by cauterization or with carbolic acid highly efficient as a prophylactic measure. Hata (30) in 1912 introduced salvarsan therapy and reported eight cases so treated, seven of which showed marked and rapid improvement. One case was apparently unaffected. Two of the cases receiving only small doses had a subsequent relapse. Surveyor (31) and Dalal (18) also have reported success with salvarsan injections. It is to be hoped that further experience with this method of treatment will yield equally favorable results.
PMCID: PMC2125348  PMID: 19867970
18.  Dapsone induced cholangitis as a part of dapsone syndrome: a case report 
BMC Gastroenterology  2003;3:21.
Dapsone can rarely cause a hypersensitivity reaction called dapsone syndrome, consisting of fever, hepatitis, exfoliative dermatitis, lymphadenopathy and hemolytic anemia. Dapsone syndrome is a manifestation of the DRESS (drug rash with eosinophilia and systemic symptoms) syndrome which is a serious condition that has been reported in association with various drugs. Cholangitis in dapsone syndrome has not been reported so far in the world literature.
Case presentation
We report a patient who presented with fever, exfoliative dermatitis, jaundice and anemia within three weeks of starting of dapsone therapy. These features are typical of dapsone syndrome, which is due to dapsone hypersensitivity and is potentially fatal. Unlike previous reports of hepatitic or cholestatic injury in dapsone syndrome we report here a case that had cholangitic liver injury. It responded to corticosteroids.
We conclude that cholangitis, though unusual, can also form a part of dapsone syndrome. Physicians should be aware of this unusual picture of potentially fatal dapsone syndrome.
PMCID: PMC194587  PMID: 12911838
19.  Tubulointerstitial Nephritis and Uveitis Syndrome in a Twelve-Year-Old Girl 
Case Reports in Pediatrics  2013;2013:652043.
Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare disorder defined by the combination of biochemical abnormalities, tubulointerstitial nephritis, and uveitis. We describe a 12-year-old female, presented with a ten-day history of fever, characterized by sudden onset and rapid spontaneous resolution in few hours, accompanied by shivering, extreme fatigue, and loss of appetite. Laboratory values were consistent with renal failure of tubular origin. Renal biopsy confirmed a tubulointerstitial nephritis, with acute tubulitis, polymorphonuclear infiltration, and microabscesses. The renal interstitium was occupied by a dense inflammatory infiltrate, consisting of lymphocytes, plasma cells, and neutrophils. Glomerular structures were preserved. Ophthalmological examination that suggested a previous asymptomatic bilateral uveitis and HLA typing (HLA-DQA1∗0101/0201 and HLA-DQB1∗0303/0503) further supported the suspect of TINU syndrome. TINU syndrome is probably an underdiagnosed disorder, responsible for many cases of idiopathic anterior uveitis in young patients, especially in those who have asymptomatic renal disease and when proper diagnostic tests are not performed at the time of presentation.
PMCID: PMC3652048  PMID: 23691408
20.  Q fever — a review 
The Canadian Veterinary Journal  1990;31(8):555-563.
Q or “query” fever is a zoonosis caused by the organism Coxiella burnetii. Cattle, sheep and goats are the most common reservoirs of this organism. The placenta of infected animals contains high numbers (up to 109/g) of C. burnetii. Aerosols occur at the time of parturition and man becomes infected following inhalation of the microorganism. The spectrum of illness in man is wide and consists of acute and chronic forms. Acute Q fever is most often a self-limited flu-like illness but may include pneumonia, hepatitis, or meningoencephalitis. Chronic Q fever almost always means endocarditis and rarely osteomyelitis. Chronic Q fever is not known to occur in animals other than man. An increased abortion and stillbirth rate are seen in infected domestic ungulates.
Four provinces (Nova Scotia, New Brunswick, Ontario and Alberta) reported cases of Q fever in 1989.
A vaccine for Q fever has recently been licensed in Australia.
PMCID: PMC1480833  PMID: 17423643
21.  Acute adrenal failure as the presenting feature of primary antiphospholipid syndrome in a child 
Antiphospholipid syndrome (APS) is characterized by recurrent arterial and venous thrombosis and detection of antiphospholipid antibodies (aPLs). This syndrome may be associated with connective tissue disorders, or with malignancies, but it may also appear in isolated form (primary APS). We report on a pediatric patient presenting with acute adrenal failure as the first manifestation of primary APS.
Case report
A previously healthy 11-year-old boy developed fever, abdominal pain, and vomiting. An abdominal computed tomography scan showed nodular lesions in the adrenal glands. He was referred to our Department and a diagnosis of APS and acute adrenal failure was considered, based on positive aPLs (IgG and IgM), elevated ACTH levels and low cortisol levels. Other features were anemia, thrombocytopenia, elevated inflammatory parameters, hypergammaglobulinemia, prolonged partial thromboplastin time, positive antinuclear, anticardiolipin, anti-platelet antibodies, with negative double-stranded DNA antibodies. Lupus anticoagulant and Coomb’s tests were positive. MRI revealed a bilateral adrenal hemorrhage. A treatment with intravenous metylprednisolone, followed by oral prednisone and anticoagulant, was started, resulting in a progressive improvement. After 2 months he also showed hyponatremia and elevated renine levels, indicating a mineralcocorticoid deficiency, requiring fludrocortisones therapy.
The development of acute adrenal failure from bilateral adrenal haemorrhage in the context of APS is a rare but life-threatening event that should be promptly recognized and treated. Moreover, this case emphasizes the importance of the assessment of aPLs in patients with acute adrenal failure in the context of an autoreaction.
PMCID: PMC3481365  PMID: 22995124
Adrenal insufficiency; Adrenal hemorrhage; Antiphospholipid syndrome; Thrombotic events
22.  Epidemiology of Coxiella burnetii Infection in Africa: A OneHealth Systematic Review 
Q fever is a common cause of febrile illness and community-acquired pneumonia in resource-limited settings. Coxiella burnetii, the causative pathogen, is transmitted among varied host species, but the epidemiology of the organism in Africa is poorly understood. We conducted a systematic review of C. burnetii epidemiology in Africa from a “One Health” perspective to synthesize the published data and identify knowledge gaps.
Methods/Principal Findings
We searched nine databases to identify articles relevant to four key aspects of C. burnetii epidemiology in human and animal populations in Africa: infection prevalence; disease incidence; transmission risk factors; and infection control efforts. We identified 929 unique articles, 100 of which remained after full-text review. Of these, 41 articles describing 51 studies qualified for data extraction. Animal seroprevalence studies revealed infection by C. burnetii (≤13%) among cattle except for studies in Western and Middle Africa (18–55%). Small ruminant seroprevalence ranged from 11–33%. Human seroprevalence was <8% with the exception of studies among children and in Egypt (10–32%). Close contact with camels and rural residence were associated with increased seropositivity among humans. C. burnetii infection has been associated with livestock abortion. In human cohort studies, Q fever accounted for 2–9% of febrile illness hospitalizations and 1–3% of infective endocarditis cases. We found no studies of disease incidence estimates or disease control efforts.
C. burnetii infection is detected in humans and in a wide range of animal species across Africa, but seroprevalence varies widely by species and location. Risk factors underlying this variability are poorly understood as is the role of C. burnetii in livestock abortion. Q fever consistently accounts for a notable proportion of undifferentiated human febrile illness and infective endocarditis in cohort studies, but incidence estimates are lacking. C. burnetii presents a real yet underappreciated threat to human and animal health throughout Africa.
Author Summary
Coxiella burnetii is a bacterium that can cause acute and chronic fever illness and pneumonia in humans. It is also a known cause of abortion in livestock species, and is principally transmitted to humans through contact with infected animal birth products. With growing awareness of the over-diagnosis and misclassification of malaria as the cause of fever illnesses in the tropics, including Africa, there is increased interest in the role of non-malarial causes of fever, such as C. burnetii. We performed a systematic review of the published literature on the epidemiology of C. burnetii in Africa to consolidate knowledge and identify knowledge gaps regarding the extent of this infection in humans and animals and the risk factors for infection transmission. Few studies on prevalence of infection in humans and animals used random sampling strategies, and among these only two studied linked human and animal populations. C. burnetii appears to be a common cause of severe fever illness in humans, but population-level incidence estimates are lacking. The differential risks for C. burnetii infection and potential control strategies within the various animal husbandry systems in Africa remain largely unexplored. We conclude that C. burnetii is an underappreciated threat to human and animal health throughout Africa.
PMCID: PMC3983093  PMID: 24722554
23.  A Success Story Leading Us to Think Big! 
Case Reports in Hematology  2011;2011:215675.
Immune dysregulation is the hallmark of all autoimmune diseases. It is extremely interesting to study the associations and pathogenesis of the various autoimmune diseases, like the link between the AIHA and CLL. This link is well established and is based on the fact that there is loss of tolerance to the self-antigen, which in turn leads to immunebased hemolytic anemia. Around 30% of the patients with CLL are at the risk of developing AIHA, and 11% eventually develop AIHA. Whether there is any definite linkup between the corrupted immune system and “acute” leukemias/lymphomas is yet to be established. Needless to say, if there was an association between the pathogenesis of the ALLs and AIHA, it would be a landmark in the field of oncology as it would enforce early diagnosis and treatment for the disease which is much more aggressive and found in a comparatively younger age group (predominantly in children and a mean age of 40 years in adults) as compared to its chronic counterparts. The AIHA would serve as a “tip to the underlying iceberg” in these situations, warning us of the cryptic diagnosis.
PMCID: PMC3420581  PMID: 22937301
24.  Tuberculous Pericarditis Presenting as Multiple Free Floating Masses in Pericardial Effusion 
Journal of Korean Medical Science  2012;27(3):325-328.
Pericarditis is a rare manifestation of tuberculosis (Tb) in children. A 14-yr-old Korean boy presented with cardiac tamponade during treatment of pulmonary tuberculosis. He developed worsening anemia and persistent fever in spite of anti-tuberculosis medications. Echocardiography found free floating multiple discoid masses in the pericardial effusion. The masses and exudates were removed by pericardiostomy. The masses were composed of pink, amorphous meshwork of threads admixed with degenerated red blood cells and leukocytes with numerous acid-fast bacilli, which were confirmed as Mycobacterium species by polymerase chain reaction. The persistent fever and anemia were controlled after pericardiostomy. This is the report of a unique manifestation of Tb pericarditis as free floating masses in the effusion with impending tamponade.
PMCID: PMC3286783  PMID: 22379347
Pericarditis; Tuberculosis; Pericardial Effusion; Cardiac Tamponade
25.  Activation and Differentiation of Autoreactive B-1 Cells by Interleukin 10 Induce Autoimmune Hemolytic Anemia in Fas-deficient Antierythrocyte Immunoglobulin Transgenic Mice 
The Fas (CD95) gene is among critical genetic factors in some autoimmune diseases, which are characterized by autoantibody (autoAb) productions. In mice, mutations in the Fas gene cause lymphoproliferation (lpr) which predominantly develops glomerulonephritis, whereas the mutations in human cause autoimmune lymphoproliferative syndrome (ALPS) characterized by autoimmune hemolytic anemia (AIHA) and thrombocytopenia. Although the mechanism of antinuclear Ab in Fas-deficient background has been well characterized, that of antierythrocyte Ab production in ALPS has been still unclear. To investigate this mechanism, we developed a mouse line by crossing the antierythrocyte antibody transgenic mice (H+L6 mice) and Fas-deficient mice. Although Fas deficiency did not break tolerance of autoreactive B-2 cells in H+L6 mice, autoreactive B-1 cells in Fas-deficient H+L6 homozygous mice became activated and differentiated into autoAb-producing cells in mesenteric lymph nodes and lamina propria of intestine, resulting in severe anemia. In addition, serum levels of interleukin (IL)-10 significantly increased in Fas−/− × H+L6 homozygous mice and administration of anti–IL-10 Ab prevented exacerbation of autoAb production and AIHA. These results suggest that activation of B-1 cells is responsible for induction of AIHA in Fas-deficient condition and that IL-10 plays a critical role in terminal differentiation of B-1 cells in these mice.
PMCID: PMC2194013  PMID: 12093879
autoantigen; autoantibody; B cell tolerance; autoimmune lymphoproliferative syndrome; peritoneal cavity

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