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 prophylaxis.
The patient’s symptoms started on September 23, 2005, with fever as high as 39°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°C), and a physical examination showed diffuse macular 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, hepatitis A, B, and C, West Nile virus, 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 (40/min), oliguria, and generalized convulsions 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, 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°C for further study.
At autopsy, jaundice and edema with diffuse hemorrhagic rash, including the conjunctivae, were evident. Internal organs were congested, 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. The cerebral cortex showed perivascular hemorrhages. Inflammatory cell infiltrates and occasional thrombi in the alveolar capillaries and arterioles 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 (Atlanta, GA, USA) (3
) showed spotted fever group rickettsiae in the vascular endothelial cells of the patient’s brain and kidney (). 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 ().
A small vessel in the kidney (A) and a capillary in the cerbral cortex (B) positive with immunohistochemical stain specific for spotted fever group rickettsiae. Original magnification ×158.
Diagnostic tests performed to identify spotted fever in the patient*
Results of nested PCR tests for spotted fever group rickettsiae (SFGR), performed at the Israeli National Reference Laboratory for Rickettsial Diseases on DNA 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 (). Bfa
I restriction profile of 17-kDa protein gene amplicons consisted of 2 fragments, 50 and 164 bp that were identical to that of R
and R. conorii
). A 208-bp fragment of the conserved 17 kDa Rickettsia
spp. antigen gene was amplified at CDC 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 as described (9
). Nucleotide sequences of each of the 4 ompA
amplicons (GenBank accession no. EU122392) and R. conorii
) were identical.
Figure 2 PCR product from the 17-kDa protein antigen gene obtained from DNA extracted from necropsied tissues of the patient. Primary PCR (A), nested PCR (B), and BfaI restriction enzyme pattern of the 17-kDa protein gene amplicon (C). Lane 1, reagent control; (more ...)