Fatal Rickettsia conorii subsp. israelensis infection, Israel.
Underdiagnosis of fatal spotted fever may be attributed to nonspecific clinical features and insensitive acute-phase serologic studies. We describe the importance of molecular and immunohistochemical methods in establishing the postmortem diagnosis of locally acquired Israeli spotted fever due to Rickettsia conorii subsp, israelensis in a traveler returning to Israel from India.
Rickettsia conorii subspecies israelensis, the cause of Israeli spotted fever (ISF), has been described in Israel, Italy, and Portugal. ISF is characterized by fever, headache, and rash after a tick bite (1,2). Since nonspecific clinical symptoms occur during disease onset, and no eschar eschar /es·char/ (es´kahr)
1. a slough produced by a thermal burn, by a corrosive application, or by gangrene.
2. tache noire.
n. is present in most Israeli cases, ISF, like other rickettsioses Rickettsioses
Often severe infectious diseases caused by several diverse and specialized bacteria, the rickettsiae and rickettsia-like organisms. The best-known rickettsial diseases infect humans and are usually transmitted by parasitic arthropod vectors. , may be misdiagnosed. Fatal outcome has been described in previously healthy children and adults, particularly when appropriate and timely antimicrobial drug treatment was not administered (2).
Serologic tests are the most widely available diagnostic tools for spotted fever, but they are less than optimal for the diagnosis of rickettsial diseases in the acute phases (3). Autopsy findings may be nondiagnostic unless specialized molecular and immunohistochemical techniques or cell culture-based methods are used to detect rickettsiae (3-5). We report a confirmed case of fatal spotted fever in Israel due to R. conorii subsp, israelensis.
A 51-year-old previously healthy Israeli man was admitted to Assaf Harofeh Medical Center in Israel for febrile illness 1 month after he had returned from a trip to India. The patient lived in an urban environment in Israel and owned a dog. He had made two 1-month long business trips to India in March and in August 2005. He had been vaccinated against hepatitis A and typhoid fever, but had not taken antimalarial antimalarial /an·ti·ma·lar·i·al/ (-mah-lar´e-al) therapeutically effective against malaria, or an agent with this quality.
Preventing or relieving the symptoms of malaria. prophylaxis.
The patient's symptoms started on September 23, 2005, with fever [approximately equal to] 39[degrees]C accompanied by headache, weakness, and frequent urination. After he was given cefuroxime sodium, a generalized rash developed. He was then referred to the hospital on September 26. On admission, he was febrile (38.9[degrees]C), and a physical examination showed diffuse macular macular adjective Related to 1. A macule 2. The macula rash on the trunk, extremities, the palms of his hands, and the soles of his feet. An allergy to cephalosporins was suspected and cefuroxime was discontinued. Results of the following studies were nondiagnostic: routine blood and urine cultures; blood smears for malaria parasites; and serologic tests for HIV HIV (Human Immunodeficiency Virus), either of two closely related retroviruses that invade T-helper lymphocytes and are responsible for AIDS. There are two types of HIV: HIV-1 and HIV-2. HIV-1 is responsible for the vast majority of AIDS in the United States. , hepatitis A, B, and C, West Nile virus West Nile virus, microorganism and the infection resulting from it, which typically produces no symptoms or a flulike condition. The virus is a flavivirus and is related to a number of viruses that cause encephalitis. , dengue virus, Leptospira spp., cytomegalovirus, and Epstein-Barr virus. The patient's condition worsened; on day 4 of hospitalization, severe muscle pain, tachycardia (189/min), tachypnea tachypnea /tach·yp·nea/ (tak?ip-ne´ah) very rapid respiration.
Rapid breathing. Also called polypnea. (40/min), oliguria oliguria /ol·i·gu·ria/ (ol?i-gu´re-ah) diminished urine production and excretion in relation to fluid intake.oligu´ric
Abnormally slight or infrequent urination. , and generalized convulsions Convulsions
Also termed seizures; a sudden violent contraction of a group of muscles.
Mentioned in: Heat Disorders had developed. Intravenous piperacillin-tazobactam (4.5 g 3 times a day) plus oral doxycycline (100 mg twice a day) were initiated. Later that day the patient experienced respiratory failure and was transferred to the intensive care unit. During the days that followed, the patient was in a deep coma with decerebrate posture and multiorgan system failure. The skin rash became overtly petechial pe·te·chi·a
n. pl. pe·te·chi·ae
A small purplish spot on a body surface, such as the skin or a mucous membrane, caused by a minute hemorrhage and often seen in typhus. , with areas compatible with purpura fulminans. Because intravenous doxycycline is not available in Israel, doxycycline tablets were administered through the nasogastric tube, combined with intravenous meropenem. The patient died on October 2, 2005, on day 11 of illness (day 8 of hospitalization, day 5 of doxycycline therapy). An autopsy was performed and serum samples and tissue from various organs were preserved at -70[degrees]C for further study.
At autopsy, jaundice and edema with diffuse hemorrhagic Hemorrhagic
A condition resulting in massive, difficult-to-control bleeding.
Mentioned in: Hantavirus Infections
pertaining to or characterized by hemorrhage. rash, including the conjunctivae Conjunctivae
The clear membranes that line the inside of the eyelids and cover the white part (sclera) of the eyeballs.
Mentioned in: Exophthalmos, Kawasaki Syndrome , were evident. Internal organs were congested con·gest·ed
Affected with or characterized by congestion.
congested ENT adjective Referring to a boggy blood-filled tissue. See Nasal congestion. , and moderate amounts of pleural fluid and ascites were noted. A pressure mark was evident on the left cerebellar tonsil, which indicated increased intracranial pressure increased intracranial pressure Intracranial hypertension, see there . The cerebral cortex showed perivascular perivascular /peri·vas·cu·lar/ (-vas´ku-lar) near or around a vessel.
around a vessel.
perivascular cellulitis hemorrhages. Inflammatory cell infiltrates and occasional thrombi thrombi /throm·bi/ (throm´bi) plural of thrombus. in the alveolar capillaries and arterioles Arterioles
Small blood vessels that carry arterial (oxygenated) blood.
Mentioned in: Retinal Artery Occlusion
n were present in the lungs. Results of staining with silver-methenamine and periodic acid-Schiff were negative for pathogens.
Immunohistochemical staining performed at the Centers for Disease Control and Prevention Centers for Disease Control and Prevention (CDC), agency of the U.S. Public Health Service since 1973, with headquarters in Atlanta; it was established in 1946 as the Communicable Disease Center. (Atlanta, GA, USA) (3) showed spotted fever group rickettsiae in the vascular endothelial cells of the patient's brain and kidney (Figure 1). Serologic tests for R. conorii from day 7 of illness yielded negative results (both immunoglobulin [Ig] M and IgG). On day 11 of illness, IgG results remained negative and IgM results were borderline positive (Table).
[FIGURE 1 OMITTED]
Results of nested PCR PCR polymerase chain reaction.
polymerase chain reaction
Polymerase chain reaction (PCR) tests for spotted fever group rickettsiae (SFGR), performed at the Israeli National Reference Laboratory for Rickettsial Diseases on DNA DNA: see nucleic acid.
or deoxyribonucleic acid
One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes. samples prepared from serum collected on day 7 of illness (8), were negative. These tests were also applied to autopsy tissue samples (liver, muscle, skin, lung, kidney) and yielded a 214-bp amplicon from the 17-kDa protein gene of the SFGR (Figure 2). BfaI restriction profile of 17-kDa protein gene amplicons consisted of 2 fragments, 50 and 164 bp that were identical to that of R. conorii subsp, conorii and R. conorii subsp, israelensis (8). A 208-bp fragment of the conserved 17-kDa 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. spp. antigen gene was amplified at CDC See Control Data, century date change and Back Orifice.
CDC - Control Data Corporation from a DNA specimen obtained from a serum sample collected during the autopsy, and indicated SFGR DNA in the patient's bloodstream. An outer membrane protein A (ompA) gene fragment (70-602 nt) was amplified from the positive serum sample extracted at CDC and from skin, liver, and muscle samples extracted at the Israel Institute for Biological Research Israel Institute for Biological Research (IIBR) is a government defense research institute specializing in biology, medicinal chemistry and environmental science. It is located in Ness Ziona, 20 kilometers south of Tel Aviv. as described (9). Nucleotide sequences of each of the 4 ompA amplicons (GenBank accession no. EU122392) and R. conorii subsp. israelensis (U43797) were identical.
This case underscores the difficulties involved in establishing the diagnosis of ISF during the acute phase of the illness. It also emphasizes the importance of considering that returning travelers may have acquired the illness locally. Although rickettsial infections can be acquired by travelers to India (10), the long incubation time (1 month) and the positive diagnosis of the etiologic agent as R. conorii subsp, israelensis makes this possibility unlikely. An endemic ISF case due to dog ownership is the more likely scenario. On the other hand, physicians caring for travelers returning from Mediterranean countries such as Italy, Portugal, and Israel should be alert to the possibility of ISF in febrile patients. Absence of eschar in ISF may be an obstacle to the correct diagnosis as exemplified by a recent case of a UK traveler to Portugal (11).
Israeli spotted fever is endemic in Israel (2). National surveillance data have been available only since the early 1970s (10). The incidence ranged from 0.7 to 10.3/100,000 (20-370 annual cases) from 1971 through 1980; it has declined steadily since 1980, reaching a nadir of 0.29/100,000 (20 cases) in 2004. The highest annual incidence reported was among children <10 years of age (10.5/100,000), and the lowest among persons >65 years (2/100,000) (12). A strong seasonal pattern exists, with the highest incidence occurring between June and October (12).
[FIGURE 2 OMITTED]
The case-fatality rate in Israel from 1971 through 1998 ranged from 0% to 3.5%, with an average rate of 0.7% (12). This rate may be an underestimate because seronegative seronegative /se·ro·neg·a·tive/ (-neg´ah-tiv) showing negative results on serological examination; showing a lack of antibody.
adj. fatal cases may not have been routinely investigated. Several examples of postmortem diagnoses in seronegative patients have been reported. In 1993, Yagupsky and Wolach described 2 children, whose postmortem diagnosis of ISF was established by using cell culture methods and animal inoculation studies (5). In 1997, 2 cases of unexplained deaths in young adults (31 and 38 years of age) were diagnosed after immunohistochemical detection of rickettsial rickettsial /rick·ett·si·al/ (ri-ket´se-al) pertaining to or caused by rickettsiae.
Relating to, or caused by a member of the genus Rickettsia. antigen in paraffin-embedded tissue obtained at autopsy (4,12). Finally, nested PCR applied to sera and tissue in several serologically unconfirmed fatal cases of R. conorii infections was shown to be effective in establishing the correct diagnosis (8,13,14). PCR performed on whole blood or skin biopsy specimens of rash collected before treatment offers the possibility of improved early and rapid laboratory diagnosis of ISF and other rickettsial infections (8,14,15).
We thank Gregory A. Dasch for discussion and review of the manuscript and Joseph Singleton for performing the microimmunofluorescence tests.
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tr.v. e·mend·ed, e·mend·ing, e·mends
To improve by critical editing: emend a faulty text. description of Rickettsia conorii. BMC (BMC Software, Inc., Houston, TX, www.bmc.com) A leading supplier of software that supports and improves the availability, performance, and recovery of applications in complex computing environments. Microbiol. 2005;5:11.
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(11.) Chai JTY, Eremeeva ME. Borland CDR (1) See CD-R and extension.
(2) (Call Detail Reporting) See call accounting.
(3) (Common Data Rate) A standard sampling rate for digital video for 480i and 576i systems. The rate is 13.5 MHz. See ITU-R BT. , Karas JA. Fatal Israeli spotted fever in a UK traveler to South Portugal. J Travel Med. 2008;15:122 3.
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A disease which can be spread from animals to humans.
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Miriam Weinberger, *([dagger]) Avi Keysary, ([double dagger]) Judith Sandbank sand·bank
A ridge of sand forming a mound, shoal, or hillside.
sandbank or sand bar
a bank of sand in a sea or river, that may be exposed at low tide
Noun 1. , * Ronit Zaidenstein, * Avi Itzhaki, * Carmela Strenger, ([double dagger]) Moshe Leitner, ([double dagger]) Christopher D. Paddock, ([section]) and Marina E. Eremeeva ([section])
* Assaf Harofeh Medical Center, Zerifin, Israel; ([dagger]) Tel Aviv University Tel Aviv University (TAU, אוניברסיטת תל־אביב, את"א) is Israel's largest on-site university. , Ramat Aviv, Israel; ([double dagger]) Israel Institute for Biological Research, Ness Ziona, Israel; and ([section]) Centers for Disease Control and Prevention, Atlanta, Georgia, USA
Address for correspondence: Miriam Weinberger, Infectious Diseases Unit, Assaf Harofeh Medical Center, Zerifin 70300, Israel; email: miriw@ netvision.net.il
Dr Weinberger is the head of the Infectious Diseases Unit at Assaf Harofeh Medical Center, Zerifin, Israel, and a senior lecturer at the Sackler School of Medicine, Tel Aviv University. Her current research interest is the epidemiology of infectious diseases with a focus on zoonotic and foodborne infections.
Table. Diagnostic tests performed to identify spotted fever in the patient * Day after disease Specimen(s) onset Assay tested Result Laboratory 7 IFA Serum IgM<100, IIBR ([dagger]) IgG<100 PCR Serum Negative IIBR 11 IFA Serum IgM = 64, CDC ([double (autopsy) IgG<32 dagger]) PCR Serum sediment Rickettsia CDC conorii subsp. israelensis Liver, muscle, Spotted fever IIBR ([section]) skin, lung, group kidney rickettsiae Liver, muscle, R. conorii CDC ([paragraph]) skin subsp. israelensis IHC Brain, kidney Positive CDC stain (#) Cell Liver, lung Negative IIBR culture ** * IFA, immunofluorescent assay; Ig, immunoglobulin; IIBR, Institute for Biological Research; CDC, Centers for Disease Control and Prevention, IHC, immunohistochemical. ([dagger]) IFA performed (6). Cutoff values for IgM and IgG are 100. ([double dagger]) IFA performed (7). Cutoff values for IgM and IgG are 64. ([section]) Nested PCR for 17-kDa protein gene (8). ([paragraph]) Nested and semi-nested PCR for 17 kDa protein gene and recombinant outer membrane protein A gene fragment, respectively, followed by sequencing (9). (#) Three-micron sections cut from formalin-fixed, paraffin-embedded brain and kidney tissue samples were stained by using an immunoalkaline phosphatase technique with a hyperimmune rabbit anti-Rickettsia rickettsii antibody at a dilution of <500 (3). ** Homogenized samples from lung and liver were applied by centrifugation onto monolayer of Vero cells culture in 24-well plates and incubated for 2 weeks at 35[degrees]C in 5% C[O.sub.2] atmosphere incubator.