Case 5 -

Maculatum Infection (Rickettsia parkeri rickettsiosis) Christopher D. Paddock Centers for Disease Control and Prevention Atlanta, GA

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Clinical Summary A 78 year-old woman-from northern Maryland presented to her physician in August 2006 following several days of fever, headache, myalgia, nausea, vomiting, and a generalized maculopapular rash. Physical examination revealed a temperature of 99.7° F and >50 small (5 to 6 mm), nonpruritic maculopapules involving her trunk and extremities, including her palms. A 1 × 1 cm, nontender, nonpruritic, ulcerated lesion with central necrosis was also identified on her right upper back. There was no adenopathy. Her serum alanine aminotranferase (ALT) and aspartate aminotransferase (AST) levels were mildly elevated at 38 U/L and 41 U/L, respectively. Her white blood cell and platelet counts were within normal limits. During the weeks preceding her illness, the patient had not traveled out of the United States, and she did not recall a specific arthropod bite or exposure. The patient was admitted to a hospital with diagnosis of Rocky Mountain spotted fever and started on intravenous doxycycline, with rapid resolution of her fever. A 4 mm punch biopsy of the necrotic lesion on her back was obtained. The specimen was bisected with one portion submitted for routine histopathology, and the other submitted to the Centers for Disease Control and Prevention (CDC) for further diagnostic evaluation. Case 5 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 5 - Figure 1 Skin punch biopsy specimen with extensive, superficial and deep, perivascular inflammatory infiltrates and focal necrosis and ulceration of the epidermis (H&E). Case 5 - Figure 2 Necrosis of the superficial dermis and partially occlusive fibrin thrombi in small vessels of the subjacent tissue (H&E). Case 5 - Figure 3 Perivascular inflammatory cell infiltrate comprised predominantly of lymphocytes and macrophages; involved vessels exhibit prominent swelling of endothelial cells (H&E). Case 5 - Figure 4 Infiltrates extending into the panniculus and eccrine ducts (H&E). Case 5 - Figure 5 Immunohistochemical stain for spotted fever group rickettsiae identifying scattered collections of intracellular coccobacilli within the inflammatory infiltrates. Microscopic description The punch biopsy specimen was remarkable for extensive, superficial and deep, perivascular inflammatory infiltrates and focal necrosis and ulceration of the epidermis (Fig. 1) accompanied by necrosis of the superficial dermis and partially occlusive fibrin thrombi in small vessels of the subjacent tissue (Fig. 2). The perivascular inflammatory cell infiltrate was comprised predominantly of lymphocytes and macrophages, and involved vessels exhibited prominent swelling of endothelial cells (Fig 3). In some areas, the infiltrate also involved the panniculus and sweat ducts (Fig. 4). An immunohistochemical stain for spotted fever group rickettsiae was used to identify scattered collections of intracellular coccobacilli within the inflammatory infiltrates (Fig. 5). DNA was extracted from formalin-fixed, paraffin-embedded sections and evaluated by using a PCR assay targeting the rompA gene of spotted fever group rickettsiae. An amplicon of the appropriate size was obtained and sequenced, and showed 100% identity with the corresponding segment of the rompA gene of Rickettsia parkeri. Diagnosis Maculatum Infection (Rickettsia parkeri rickettsiosis) Discussion Background Maculatum infection, a newly recognized spotted fever rickettsiosis caused by Rickettsia parkeri, causes a febrile, rash-associated illness that shares many clinical and epidemiologic features with Rocky Mountain spotted fever. R. parkeri is an example of a bacterium known to science for many decades (in this case, since the late 1930s), but was not identified as a pathogen of humans until 2004; In this context, R. parkeri rickettsiosis can be considered legitimately an emerging infection [1]. R. parkeri is named in honor of Ralph R. Parker, a pioneering rickettsiologist who discovered the agent in 1939. Parker also was the first to recognize the disease potential of this agent, and applied the term 'maculatum infection' to the illness observed in animals experimentally infected with this rickettsia. Epidemiology R. parkeri is transmitted by the bite of the Gulf Coast tick (Amblyomma maculatum). This tick is distributed predominantly in coastal regions of U.S. states that border the Gulf of Mexico and mid-to-south Atlantic region. To date, 12 cases of confirmed or probable maculatum infection have been identified in patients from 7 states within the range of the Gulf Coast tick. Cases have been reported during April-September, but most have been identified during late July-late August. Maculatum infection shares many clinical similarities with RMSF, including fever, headache, rash, and myalgias, but appears to be far less severe than RMSF, with fewer hospitalized cases and no associated deaths. The occurrence of an eschar is a prominent distinguishing feature, because eschars are only rarely noted in well-characterized cases of RMSF [2]. To date, confirmed cases of maculatum infection have been reported from only the United States; however, R. parkeri has been detected in human biting ticks from several South American countries including Brazil and Uruguay, and it is likely that many cases of 'RMSF' diagnosed in the Western hemisphere represent cases of maculatum infection [3]. Differential diagnoses Eschars can been seen in various infectious and noninfectious conditions that include other spotted fever rickettsioses (e.g., rickettsialpox and African tick bite fever), viral infections (e.g., herpes simplex and varicella-zoster), cutaneous anthrax, plague, tularemia, leishmaniasis, and localized fungal infections [4, 5], as well as arthropod assaults (e.g., spider envenomations, localized hypersensitivity reactions, and embedded mouthparts) [6, 7, 8]. A sparse papulovesicular eruption, typical of patients with maculatum infection, can also occur in rickettsialpox, African tick bite fever, varicella, and infections caused by various enteroviruses, including echoviruses 9 and 16, coxsackieviruses A9, A16, and B5. However, the disease that is most often confused with maculatum infection is RMSF; from a recent series of 12 patients with confirmed and probable maculatum infection, RMSF was considered in the working diagnosis at the time that specimens were submitted to CDC for laboratory tests [CDC, unpublished]. The histopathologic features of maculatum infection are similar to those described for other eschar-associated rickettsioses [4, 9]. The eschar shows extensively denuded epithelium with necrosis that often extends into the superficial to middle levels of the dermis (Figs. 1 and 2). A dense, mixed perivascular inflammatory cell infiltrate involves the full thickness of the dermis (Fig. 1) and is comprised predominantly of lymphocytes and macrophages (Fig. 3), although a prominent neutrophilic component to the infiltrates can be seen in many early lesions. The infiltrates typically involve the adnexae and may extend into the subcutaneous fat (Fig. 4). Rash lesions also show mixed perivascular infiltrates, but the epidermis is intact or may reveal a small intraepidermal pustule or vesicle. In contrast to most arthropod assaults, eosinophils are not a prominent component of the infiltrate. Histopathologic distinction from the cutaneous rash of RMSF can be subtle; however, features such as neutrophil-rich infiltrates, epidermal necrosis, inflammatory involvement of adnexae or the panniculus, or vesicle or pustule formation, are not described or only seldom noted with RMSF [10]. Laboratory Tests Various serologic assays are widely available to confirm rickettsial illnesses to the general level of 'spotted fever rickettsiosis'. The most widely applied method is the indirect immunofluorescence antibody (IFA) assay, using one or more serum specimens collected during the acute and convalescent phases of the illness. The test is suitably sensitive when appropriately collected samples are obtained; however, antibodies are generally absent during the first week of illness, which may necessitate the return of the patient for evaluation. Also, this assay does not differentiate R. parkeri infection from any of the other spotted fever rickettsial pathogens indigenous to the U.S. including R. rickettsii (the cause of RMSF) and Rickettsia akari (the cause of rickettsialpox). The most definitive method of obtaining a species-specific diagnosis requires collection of a punch biopsy specimen from an eschar or rash lesion [1, 2, 4]. This sample can be processed by a variety of methods, including cell culture isolation, PCR, and immunohistochemical (IHC) staining for spotted fever group rickettsiae. These assays are generally only available at specialized rickettsial reference centers, including the Centers for Disease Control and Prevention; however, any laboratory that performs viral isolation is theoretically equipped to isolate rickettsiae from clinical specimens if appropriate biosafety precautions are followed [4]. Tissues processed for routine histopathologic evaluation are also suitable for IHC and PCR tests. Rickettsiae do not stain well with most routine histochemical stains for bacteria. IHC stains for spotted fever group rickettsiae, including R. parkeri, provide excellent visualization of the pathogen in tissues specimens; however, these stains are not species-specific, and as with current serologic assays, can only confirm infection with a spotted fever rickettsia to the group level [11, 12]. Treatment Patients respond rapidly (typically within 12-24 h) to therapy with a tetracycline-class antibiotic. Doxycyline (100 mg p.o. bid) for a minimum of 5 days is considered the treatment of choice for adults and children with rickettsial diseases. To date, no other antibiotics have been conclusively identified as effective alternate therapy for maculatum infection. References Paddock CD, Sumner JW, Comer JA, et al. Rickettsia parkeri: a newly recognized cause of spotted fever rickettsiosis in the United States. Clin Infect Dis 2004;38: 805-11. Walker DH Gay RM, Valdes-Dapena M. The occurrence of eschars in Rocky Mountain spotted fever. J Am Acad Dermatol 1981;4: 571-6. Paddock CD. Rickettsia parkeri as a paradigm for multiple causes of tick-borne rickettsioses in the Western Hemisphere. Ann NY Acad Sci 2006;1063:315-26. Paddock CD, Koss T, Eremeeva ME, Dasch GE, Zaki SR, Sumner JW. Isolation of Rickettsia akari from eschars of patients with rickettsialpox. Am J Trop Med Hyg 2006;75:732-8. Shieh W-J, Guarner J, Paddock C, et al. The critical role of pathology in the investigation of bioterrorism-related cutaneous anthrax.Am J Pathol 2003;163:1901-10. Elston DM, Eggers JS, Schmidt WE, et al. Histological findings after brown recluse spider envenomation. Am J Dermatopathol 2000;22:242-6. Veraldi S, Barbareschi M, Zerboni R, Scarabelli G. Skin manifestations caused by pigeon ticks (Argas reflexus). Cutis 1998;61:38-40. Pajvani U, Zeikus PS, Basile O, Toback N, Robinson-Bostom L. Thrombogenic vasculopathy with difuse neutrophilic inflammation: a histologic manifestation of tick bite. Cutis 2006;78:321-4. Lepidi H, Fournier PE, Raoult D. Histologic features and immunodetection of African tick-bite fever. Emerg Infect Dis 2006;12:1332-7. Kao GF, Evancho CD, Ioffe O, Lowitt MH, Dumler JS. Cutaneous pathology of Rocky Mountain spotted fever. J Cutaneous Pathol 1997;24:604-10. Dumler JS, Gage WR, Pettsi GL, Azad AF, Kuhadja FP. Rapid immunoperoxidase demonstration of Rickettsia rickettsii in fixed cutaneous specimens from patients with Rocky Mountain spotted fever. Am J Clin Pathol 1990;93:410-4. Paddock CD, Greer PW, Ferebee TL, et al. Hidden mortality attributable to Rocky Mountain spotted fever: immunohistochemical detection of fatal, serologically unconfirmed disease. J Infect Dis 1999; 179:1469-76.