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 typhi or other cross-reactive species.

The Study

Murine or endemic typhus is caused by Rickettsia typhi, formerly R. mooseri (1). Classic murine typhus is a zoonosis 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).

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 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 diagnosis of routine typhus 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 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 distribution, was a frequent finding (68.2%). Up to one third of the patients had a dry cough. Hepatomegaly and, less frequently, splenomegaly 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 was detected in two patients, and mild leukocytosis in four patients. Ten case-patients (45%) had thrombocytopenia. In most patients (89.5%), the erythrocyte sedimentation rate was high (11-83 mm/h), and the activated partial thromboplastin time (aPTT) was prolonged in six patients.

Aminotransferase 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 was normal for all patients.

In 36% of the patients, the plasma blood urea nitrogen 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 and microhematuria with or without leukocyturia and granular casts, with a negative nitrite 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), 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 (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 (plasma creatinine 2.8% mg), microhematuria, and leukocyturia. Intravenous fluids, doxycycline, ciprofloxacin, and methylprednisolone (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. A cranial contrast computed tomography scan was normal, and cerebrospinal fluid (CSF) showed mononuclear pleocytosis (90 cells/[micro]L), protein 70 mg/dL, and normal glucose. Doxycycline was administered with rapid neurologic improvement. Conjunctivitis and rash appeared but waned shortly after. Finally, patient 21 had a progressive meningeal 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, boutonneuse fever, leptospirosis, 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, which requires time for confirmation. Therefore, in the meantime, 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 [6] and Silpapojakul [11]), 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 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 deficiency.

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).

Conclusions

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.

References

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(14.) Rosenthal T, Michaeli D. Murine typhus and spotted fever in Israel in the seventies. Infection 1977;5:82-4.

(15.) Whelton A, Douglas JV, Elisberg BI. Acute renal failure complicating rickettsial infection in glucose-6-phosphate dehydrogenase deficient individuals. Ann Intern Med 1968;69:323-8.

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, 35080, Canary Islands, Spain; fax: [phone]; email: [e-mail]

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