Murine typhus with renal involvement in Canary Islands, Spain.Murine typhus and "murine-typhus-like" disease are reemerging infectious diseases. In Canary Islands (Spain), a rather distinct clinical pattern characterized by higher incidence of complications, especially renal damage (including acute failure and urinalysis abnormalities), is apparent and highly suggestive. It could be related to different strains of Rickettsia rickettsia (rĭkĕt`sēə), any of a group of very small microorganisms, many disease-causing, that live in vertebrates and are transmitted by bloodsucking parasitic arthropods such as fleas, lice (see louse), and ticks. typhi or other cross-reactive species.
Murine or endemic typhus is caused by Rickettsia typhi, formerly R. mooseri (1). Classic murine typhus is a zoonosis Zoonosis Definition
Zoonosis, also called zoonotic disease refers to diseases that can be passed from animals, whether wild or domesticated, to humans. maintained in rats (Rattus rattus and Rattus nolwergicus) and transmitted to humans through damaged skin by infected feces from the oriental rat flea (Xenopsylla cheopis) (2). New patterns of disease ("murine typhus-like" disease) have been described in recent years, and a new species of Rickettsia (R. felis) that causes a similar clinical picture has been identified (1-3). New modes of infection have been identified, including infection through inhalation of flea feces and transmission by different types of fleas (Ctenophtephalis felis) and from different reservoirs (e.g., dog, cat, and opossum opossum (əpŏs`əm, pŏs`–), name for several marsupials, or pouched mammals, of the family Didelphidae, native to Central and South America, with one species extending N to the United States. ).
Murine typhus occurs worldwide, particularly in warm and humid climates (1). In Spain, two seroepidemiologic surveys, in Salamanca and Madrid (Central/Western Spain), yielded seroprevalence rates of 12.8% and 68%, respectively, in the general population (4,5). However, no clinical cases have been reported. In Seville (Southwestern Spain), murine typhus is an important cause of fever of intermediate duration (6), and in Canary Islands, 10 autochthonous autochthonous /au·toch·tho·nous/ (aw-tok´thah-nus)
1. originating in the same area in which it is found.
2. denoting a tissue graft to a new site on the same individual. cases have been reported from Tenerife (7). For this reason, we include serologic testing for R. typhi in the evaluation of patients with fever of intermediate duration. We describe the clinical picture of murine typhus in the Canary Islands.
Adult ([greater than or equal to] 14 years of age) inpatients and outpatients at the Hospital Universitario Insular of Las Palmas with a serologic se·rol·o·gy
n. pl. se·rol·o·gies
1. The science that deals with the properties and reactions of serums, especially blood serum.
2. diagnosis of routine typhus typhus, any of a group of infectious diseases caused by microorganisms classified between bacteria and viruses, known as rickettsias. Typhus diseases are characterized by high fever and an early onset of rash and headache. during December 1, 2000, through July 30, 2002, were included in our study. A case was defined by an immunoglobulin (Ig) M titer [greater than or equal to] 1:40, or a fourfold or higher increase in IgG titers against R. typhi by direct immunofluorescence Immunofluorescence
A technique that uses a fluorochrome to indicate the occurrence of a specific antigen-antibody reaction. The fluorochrome labels either an antigen or an antibody. test in 8 weeks (bioMerieux, France), or both.
Epidemiologic, clinical, and laboratory data were collected. Antibodies against other agents that may cause a fever of intermediate duration (e.g., Coxiella burnetii, R. conorii, Leptospira sp., Epstein-Barr virus, and cytomegalovirus) were systematically tested. Twenty-two patients (21 men, 1 woman), with a mean age of 28 years (range 14 to 76 years), were included. Marine typhus was more frequent in summer (Figure 1). No case aggregation was observed. The geographic distribution is shown in Figure 2. All patients reported contact with animals (13 with dogs, 6 with horses, 5 with goats, 2 with cats, and 1 with camels).
[FIGURES 1-2 OMITTED]
The main symptoms and signs recorded are shown in Table 1. All patients had a high fever (mean 39.3[degrees]C) during a mean of 10 days (range 7 to 20 days). A light maculopapular, nonpurpuric rash, with rather centripetal centripetal /cen·trip·e·tal/ (sen-trip´e-t'l)
1. afferent (1).
1. Moving or directed toward a center or axis. distribution, was a frequent finding (68.2%). Up to one third of the patients had a dry cough. Hepatomegaly hepatomegaly /hep·a·to·meg·a·ly/ (hep?ah-to-meg´ah-le) enlargement of the liver.
The abnormal enlargement of the liver. Also called megalohepatia. and, less frequently, splenomegaly splenomegaly /sple·no·meg·a·ly/ (-meg´ah-le) enlargement of the spleen.
congestive splenomegaly Banti's disease; splenomegaly secondary to portal hypertension. were detected. Skin lesions suggestive of insect bites were found in 13.6% of the patients.
Four patients had a mild normocytic anemia. For most patients, leukocyte counts were normal, mild leukopenia leukopenia /leu·ko·pe·nia/ (-pe´ne-ah) reduction of the number of leukocytes in the blood below about 5000 per cubic mm.leukope´nic
basophilic leukopenia basophilopenia. was detected in two patients, and mild leukocytosis Leukocytosis Definition
Leukocytosis is a condition characterized by an elevated number of white cells in the blood.
Leukocytosis is a condition that affects all types of white blood cells. in four patients. Ten case-patients (45%) had thrombocytopenia Thrombocytopenia Definition
Thrombocytopenia is an abnormal drop in the number of blood cells involved in forming blood clots. These cells are called platelets. . In most patients (89.5%), the erythrocyte sedimentation rate Erythrocyte Sedimentation Rate Definition
The erythrocyte sedimentation rate (ESR), or sedimentation rate (sed rate), is a measure of the settling of red blood cells in a tube of blood during one hour. was high (11-83 mm/h), and the activated partial thromboplastin time Activated partial thromboplastin time
Partial thromboplastin time test that uses activators to shorten the clotting time, making it more useful for heparin monitoring. (aPTT) was prolonged in six patients.
Aminotransferase aminotransferase /ami·no·trans·fer·ase/ (-trans´fer-as) transaminase.
n. elevation, usually four times above normal, was found frequently; two patients had normal values. Four patients had alanine aminotransferase values 10 times the normal value. Plasma bilirubin Bilirubin
The predominant orange pigment of bile. It is the major metabolic breakdown product of heme, the prosthetic group of hemoglobin in red blood cells, and other chromoproteins such as myoglobin, cytochrome, and catalase. was normal for all patients.
In 36% of the patients, the plasma blood urea nitrogen blood urea nitrogen
n. Abbr. BUN
Nitrogen in the form of urea in the blood or serum, used as a indicator of kidney function.
Blood urea nitrogen (BUN) was elevated; plasma creatinine was above normal in three cases (13%). In 19 cases (87%), alterations were found in the urinalysis. Fifteen patients had proteinuria proteinuria /pro·tein·uria/ (-ur´e-ah) an excess of serum proteins in the urine, as in renal disease or after strenuous exercise.proteinu´ric
1. and microhematuria with or without leukocyturia and granular casts, with a negative nitrite nitrite
Any salt or ester of nitrous acid (HNO2). The salts are inorganic compounds with ionic bonds, containing the nitrite ion (NO2−) and any cation. reaction. In two patients, isolated proteinuria occurred, and isolated microhematuria occurred in two other patients. All of these findings resolved quickly.
Eight patients fulfilled both diagnostic criteria (IgM [greater than or equal to] 1:40 plus seroconversion seroconversion /se·ro·con·ver·sion/ (-con-ver´zhun) the change of a seronegative test from negative to positive, indicating the development of antibodies in response to immunization or infection. ), eight patients had initial IgM elevation, and six seroconverted without IgM increase. Cross-reactivity between R. typhi and other microorganisms was not observed. Fifty percent of the patients had serologic evidence of past infection with C. burnetii (12/22) or R. conorii (3/22) and, in one case, of co-infection with C. burnetii.
Eight cases were not treated because of spontaneous recovery. The remaining patients received doxycycline doxycycline /doxy·cy·cline/ (dok?se-si´klen) a semisynthetic broad-spectrum tetracycline antibiotic, active against a wide range of gram-positive and gram-negative organisms; used also as d. calcium and d. hyclate. (100 mg twice a day). Fever disappeared from 1 to 6 days (median 2 days).
Three patients had severe signs and symptoms. Patient 6 was admitted with acute respiratory failure, lung infiltrates, and acute renal failure acute renal failure Acute kidney failure Nephrology An abrupt decline in renal function, triggered by various processes–eg, sepsis, shock, trauma, kidney stones, drug toxicity-aspirin, lithium, substances of abuse, toxins, iodinated radiocontrast. (plasma creatinine 2.8% mg), microhematuria, and leukocyturia. Intravenous fluids, doxycycline, ciprofloxacin ciprofloxacin /cip·ro·flox·a·cin/ (sip?ro-flok´sah-sin) a synthetic antibacterial effective against many gram-positive and gram-negative bacteria; used as the hydrochloride salt.
n. , and methylprednisolone methylprednisolone /meth·yl·pred·nis·o·lone/ (-pred-nis´ah-lon) a synthetic glucocorticoid derived from progesterone, used in replacement therapy for adrenocortical insufficiency and as an antiinflammatory and immunosuppressant; also (1 g) were administered, and the patient rapidly improved. Autoantibodies and cryoglobulins were negative. Patient 16 had a dry cough and acute renal failure (plasma creatinine 2.7% mg) and later become disoriented dis·o·ri·ent
tr.v. dis·o·ri·ent·ed, dis·o·ri·ent·ing, dis·o·ri·ents
To cause (a person, for example) to experience disorientation.
Adj. 1. . A cranial contrast computed tomography scan Computed tomography scan (CT scan)
A specialized type of x-ray imaging that uses highly focused and relatively low energy radiation to produce detailed two-dimensional images of soft tissue structures, particularly the brain. was normal, and cerebrospinal fluid (CSF Cerebrospinal Fluid (CSF) Analysis Definition
Cerebrospinal fluid (CSF) analysis is a laboratory test to examine a sample of the fluid surrounding the brain and spinal cord. ) showed mononuclear pleocytosis pleocytosis /pleo·cy·to·sis/ (ple?o-si-to´sis) presence of a greater than normal number of cells in cerebrospinal fluid.
n. (90 cells/[micro]L), protein 70 mg/dL, and normal glucose. Doxycycline was administered with rapid neurologic improvement. Conjunctivitis conjunctivitis (kənjəngtəvī`təs), inflammation or infection of the mucosal membrane that covers the eyeball and lines the eyelid, usually acute, caused by a virus or, less often, by a bacillus, an allergic reaction, or an and rash appeared but waned shortly after. Finally, patient 21 had a progressive meningeal me·nin·ge·al
Of, relating to, or affecting the meninges.
pertaining to the meninges.
meningeal hemorrhage syndrome, CSF showed mononuclear pleocytosis (19 cells/[micro]L), increased protein (49 mg/dL), and normal glucose levels. The patient completely recovered in 48 hours after receiving doxycycline.
Fever of intermediate duration has been defined by others in Spain as fever of 7 to 28 days without localizing signs (i.e., respiratory, digestive, urinary, or neurologic), plus the absence of diagnostic clues after a complete evaluation (6). A few diseases can account for most cases of this type of fever (mainly Q fever, brucellosis brucellosis (br'səlō`sĭs) or Bang's disease, infectious disease of farm animals that is sometimes transmitted to humans. , boutonneuse fever, leptospirosis leptospirosis (lĕp'təspīrō`sĭs), febrile disease caused by bacteria of the genus Leptospirae. The disease occurs in dogs, cattle, pigs, sheep, goats, and horses and is transmissible to humans. , mononucleosic syndromes, and murine typhus). In our area, autochthonous cases of boutonneuse fever or brucellosis have never been reported. Diagnosis is usually based on serology Serology
The division of biological science concerned with antigen-antibody reactions in serum. It properly encompasses any of these reactions, but is often used in a limited sense to denote laboratory diagnostic tests, especially for syphilis. , which requires time for confirmation. Therefore, in the meantime Adv. 1. in the meantime - during the intervening time; "meanwhile I will not think about the problem"; "meantime he was attentive to his other interests"; "in the meantime the police were notified"
meantime, meanwhile , identifying clinical data for empirical treatment is important.
In our study, the number of cases per year is 12, higher than that in other areas of Spain (6), Israel (8), or the United States (9,10), with higher rate in summer. Most patients were male. All patients had direct contact with animals as reported by others (9,10); dogs were the most frequently cited animal (9,10).
The clinical features in our study are similar to those reported by others (6,9 13) with respect to those most frequent symptoms (fever, headache, and arthromyalgia) (Table 1). The incidence of rash is similar to that reported by Bernabeu (6) and Whiteford (9) and higher than that in other series. Reports of insect bites were more frequent in our study than studies from other areas (Bernabeu  and Silpapojakul ), but more insect bites were reported from a Texas study (9).
The laboratory findings in our study are similar to findings in other studies, although its relative frequency is variable (Table 2). The frequency of anemia varies from 1% to 69%, leukopenia from 4% to 40%, and thrombocytopenia from 3% to 60% (6,9,10,11). While 80% of the patients with Q fever in our area have a prolonged aPTT, 27% of the patients with murine typhus displayed this abnormal coagulation coagulation (kōăg'ylā`shən), the collecting into a mass of minute particles of a solid dispersed throughout a liquid (a sol), usually followed by the precipitation or test. An elevation of aminotransferases in the range of viral hepatitis was common, but hyperbilirubinemia is exceptional and usually associated with alcoholism, co-infection, or glucose 6-phosphate dehydrogenase dehydrogenase /de·hy·dro·gen·ase/ (de-hi´dro-jen-as?) an enzyme that catalyzes the transfer of hydrogen or electrons from a donor, oxidizing it, to an acceptor, reducing it.
Nephrologic alterations had a high frequency in our study. Three patients had acute renal failure, and 87% had some abnormality in the urinalysis, mainly microhematuria. These data are in sharp contrast with the low incidence of urinary alterations found in other studies. Some broad studies (6,9,10) do not report urinary abnormalities in murine typhus, though Dumler et al. (13) reported microhematuria or proteinuria in 28% of their patients. In a study specifically focused on renal involvement in murine typhus, Shaked et al. observed urinary abnormalities in 5 of 27 patients studied (8). To the best of our knowledge, 11 cases of acute renal failure have been related to R. typhi (9,11,14,15).
In general, murine typhus is a mild disease. However, a number of miscellaneous complications have been described. Our severe cases accounted for 13% (one renopulmonary syndrome, one encephalitis, and one meningitis with renal failure).
In summary, in the Canary Islands, incidence of murine typhus seem to be higher, patients more frequently report contact with dogs, the frequency of complicated cases is higher, and the incidence of renal involvement is higher. These data define a clinical picture of murine typhus that is somewhat different for the Canary Islands. These differences could be attributed to age (infantile versus adult series), mode of transmission or infection, or different strains of R. typhi. The diagnostic methodology was indirect, so cross-reaction with other rickettsiae cannot be excluded (11). Moreover, in our area, dogs are frequently parasitized by the flea of cats, a well-known vector for R. felis (3). More studies with direct diagnostic methods are needed to better define these differences. Finally, detecting urinary abnormalities in the setting of fever of intermediate duration, especially if associated with skin rash, thrombocytopenia, or hypertransaminasemia, in our geographic area is strongly suggestive of murine typhus.
Table 1. Clinical findings (a) Researcher and location of study Dumler, Silpapojakul, Bernabeu, Fergie, Clinical findings TX 1991 Thailand 1992 Seville 1999 TX 2000 n 80 137 104 30 Fever 98 100 100 100 Headache 75 41 71 77 Rash 54 20 62 80 Arthromyalgia 46 44 77 57 Hepatomegaly -- 24 29 -- Cough 35 -- 25 40 Diarrhea 26 5 5 40 Splenomegaly -- 5 24 -- Bite 39 0 3 3,3 Nausea/vomiting 48 3 23 43 Abdominal pain 23 10 -- 60 Confusion 8 2 4 7 Researcher and location of study Whiteford, Gikas, Canary Clinical findings TX 2001 Crete 2002 Islands 2003 n 97 83 22 Fever 100 100 100 Headache 76 88 90 Rash 63 80 -- Arthromyalgia 40 45 45 Hepatomegaly -- 22 38 Cough 15 28 28 Diarrhea 33 11 18 Splenomegaly -- 23 14 Bite 34 -- 13 Nausea/vomiting 45 18 13 Abdominal pain 27 11 13 Confusion 8 10 13 (a) Data are expressed as a percentage; TX, Texas. Table 2. Comparative laboratory findings in patients with murine typhus Researcher and location of study Dumler, Silpapojakul, Bernabeu, Laboratory test results TX Thailand Seville Anemia 75 -- 1 Leukopenia 28 4 18 Leukocytosis 29 -- 20 Neutrophilia -- -- -- Thronibocytopenia 48 3 19 ESR elevated -- -- 59 Increased ratio 30 -- -- prothrombin time Increased ratio aPTT -- -- -- Plasma BUN increased 27 -- -- Plasma creatinine increased 21 -- -- Hyponatremia 60 -- -- Plasma creatine kinase 21 -- -- increased Plasma LDH increased 87 -- -- Plasma AST increased 90 -- 67 Plasma ALT increased 73 -- 67 Plasma alkaline phosphatase 60 -- 25 increased Plasma GGT increased -- -- -- Hypoalbuminemia 89 -- -- Hypergammaglobulinemia -- -- -- Researcher and location of study Fergie, Whiteford, Gikas, Canary Laboratory test results TX TX Crete Islands Anemia 57 69 25 18 Leukopenia 40 37 7 9 Leukocytosis 3 1 0 18 Neutrophilia 63 77 -- 36 Thronibocytopenia 60 43 51 45 ESR elevated 75 81 -- 89 Increased ratio -- -- -- 23 prothrombin time Increased ratio aPTT -- -- -- 27 Plasma BUN increased 0 3 -- 36 Plasma creatinine increased 0 0 -- 14 Hyponatremia 66 58 37 18 Plasma creatine kinase -- -- 42 10 increased Plasma LDH increased -- 100 82 81 Plasma AST increased 67 82 86 77 Plasma ALT increased 67 38 64 99 Plasma alkaline phosphatase -- -- 15 30 increased Plasma GGT increased -- -- -- 57.2 Hypoalbuminemia 46 87 82 54.5 Hypergammaglobulinemia -- -- -- 75.0 (a) Data are expressed as a percentage. TX, Texas; ESR, erythrocyte sedimentation rate; aPTT, activated partial thromboplastin time; BUN, blood urea nitrogen; LDH, lactate dehydrogenase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; GGT, gamma glutamic transferase.
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Dr. Hernandez-Cabrera was an associate professor of infectious diseases and tropical medicine at Faculty of Medicine at University of Las Palmas de Gran Canaria, Spain. His research interests focus on rickettsial diseases and other causes of fever of intermediate duration.
Address for correspondence: Jose Luis Perez-Arellano, Departamento de Ciencias Medicas y Quirurgicas, Universidad de Las Palmas de Gran Canaria The University of Las Palmas de Gran Canaria, also known as the ULPGC (Spanish Universidad de Las Palmas de Gran Canaria) is a Spanish university located in Las Palmas de Gran Canaria, the capital of Gran Canaria island. , 35080, Canary Islands, Spain; fax: 928451413; email: email@example.com
Michele Hernandez-Cabrera, (1) * ([dagger)] Alfonso Angel-Moreno, (1) * ([dagger]) Evora Santana, * ([dagger]) Margarita Bolanos, * Adela Frances, * Antonio-Manuel Martin-Sanchez, * ([dagger]) and Jose Luis Perez-Arellano * ([dagger])
* Hospital Universitario Insular de Gran Canaria, Canary Islands, Spain; and ([dagger]) Universidad de Las Palmas de Gran Canaria, Canary Islands, Spain