Spotted Fever Group Rickettsioses

Etiology

RMSF results from systemic infection of endothelial cells by the obligate intracellular bacterium Rickettsia rickettsii.

Epidemiology

The term Rocky Mountain spotted fever is historical, because the agent was discovered in the Bitterroot Range of the Rocky Mountains of Montana. Few cases are reported from this region. Cases have been reported throughout the continental United States (except Vermont and Maine), southwestern Canada, Mexico, Central America, and South America, but not from outside of the Western Hemisphere. In 2010, the Centers for Disease Control and Prevention (CDC) reporting criteria for Rocky Mountain spotted fever changed to spotted fever group rickettsiosis, because serology often does not distinguish R. rickettsii from infection by other spotted fever group Rickettsia . Additionally, cases detected by enzyme immunoassay were classified as probable. Thus, in 2012, 2,802 confirmed and probable cases of spotted fever rickettsiosis were reported in Morbidity and Mortality Weekly Reports Summary of Notifiable Diseases. Unlike in prior years, most cases were reported from the west south-central states, especially from Arkansas, Oklahoma, and Missouri; high numbers of cases were also reported from North Carolina, Tennessee, Virginia, New Jersey, Georgia, Alabama, and Arizona ( Fig. 255.1 ). The incidence of RMSF cycles over 25-35 yr intervals but has generally increased over the past decades. The mean number of cases reported each year to the CDC has steadily increased (515 during 1993–1998, 946 during 1999–2004, 2,068 during 2005–2010, and 3,692 during 2011–2016), of which approximately 14% occur in those younger than 19 yr. Habitats favored by ticks, including wooded areas or coastal grassland and salt marshes, and, in the southwestern United States and Mexico, shaded areas where dogs congregate and acquire infected ticks are those that place children at increased risk for infection. Foci of intense risk for infection are found both in rural and urban areas, most recently in Mexico. Clustering of cases within families likely reflects shared environmental exposures. In the United States, 90% of cases occur between April and September, months in which humans spend the most time outdoors. The highest age-specific incidence of RMSF among children is seen in those older than 10 yr of age, with males outnumbering females; however, the highest case fatality rate for RMSF is observed in those less than 10 yr of age.

Transmission

Ticks are the natural hosts, reservoirs, and vectors of R. rickettsii and maintain the infection in nature by transovarial transmission (passage of the organism from infected ticks to their progeny). Ticks harboring rickettsiae are substantially less fecund than uninfected ticks; thus, horizontal transmission (acquisition of rickettsiae by taking a blood meal from transiently rickettsemic hosts such as small mammals or dogs) contributes to maintenance of rickettsial infections in ticks. Uninfected ticks that simultaneously feed (cofeed) with infected transmitting ticks easily become infected, even if feeding on an immune host and are also likely to be major contributors to natural transmission and maintenance. Ticks transmit the infectious agent to mammalian hosts (including humans) via infected saliva during feeding. The pathogen R. rickettsii in ticks becomes virulent after exposure to blood or increased temperature; thus, the longer the tick is attached, the greater the risk of transmission. The principal tick hosts of R. rickettsii are Dermacentor variabilis (the American dog tick) in the eastern United States and Canada, Dermacentor andersoni (the wood tick) in the western United States and Canada, Rhipicephalus sanguineus (the common brown dog tick) in the southwestern United States and in Mexico, and Amblyomma cajennense and Amblyomma aureolatum in Central and South America ( Fig. 255.2 ).

Dogs can serve as reservoir hosts for R. rickettsii, can develop RMSF themselves, and can bring infected ticks into contact with humans. Serologic studies suggest that many patients with RMSF likely acquired the illness from ticks carried by the family dog.

Humans can also become infected when trying to remove an attached tick, because R. rickettsii –containing tick fluids or feces can be rubbed into the open wound at the bite site or into the conjunctivae by contaminated fingers. Inhalation of aerosolized rickettsiae has caused severe infections and deaths in laboratory workers, highlighting another mechanism of infection.

Pathology and Pathogenesis

Systemic infection is most obvious on the skin (rash), but nearly all organs and tissues are affected. Following inoculation of tick saliva into the dermis, rickettsial outer surface proteins bind to the vascular endothelial cell surface proteins, which signals focal cytoskeletal changes and endocytosis. Thereafter, rickettsia phospholipase-mediated dissolution of the endosomal membranes allows escape into the cytosol. Members of the spotted fever group actively nucleate actin polymerization on 1 pole to achieve directional movement, allowing some rickettsiae to propel into neighboring cells despite minimal initial damage to its host cell. The rickettsiae proliferate and damage the host cells by oxidative membrane alterations, protease activation, or continued phospholipase activity. It is likely that some aspects of intracellular infection are mediated by rickettsial protein effectors delivered into the host cell by bacterial secretion systems.

The histologic correlate of the initial macular or maculopapular rash is perivascular infiltration of lymphoid and histiocytic cells with edema but without significant endothelial damage. Proliferation of rickettsiae within the cytoplasm of infected endothelial cells leads to endothelial injury and lymphohistiocytic or leukocytoclastic vasculitis of small venules and capillaries, which allows extravasation of intravascular erythrocytes into the dermis and manifests as a petechial rash ( Fig. 255.3 ). This process is systemic and ultimately results in widespread microvascular leakage, tissue hypoperfusion, and possibly end-organ ischemic injury. Infrequently, inflammation leads to nonocclusive thrombi. Very rarely, small and large vessels become completely obliterated by thrombi, leading to tissue infarction or hemorrhagic necrosis. Interstitial pneumonitis and vascular leakage in the lungs can lead to non-cardiogenic pulmonary edema, and meningoencephalitis can cause significant cerebral edema and herniation.

The presence of the infectious agent initiates an inflammatory cascade, including release of cytokines and chemokines such as tumor necrosis factor-α, interleukin-1β, interferon-γ, and regulated upon activation, normal T-cell expressed and secreted (RANTES). Infection of endothelial cells by R. rickettsii induces surface E-selectin expression and procoagulant activity followed by chemokine recruitment of lymphocytes, macrophages, and, occasionally, neutrophils. Local inflammatory and immune responses are suspected to contribute to the vascular injury; however, the benefits of effective inflammation and immunity are greater. Blockade of tumor necrosis factor-α and interferon-γ action in animal models diminishes survival and increases morbidity; reactive oxygen intermediates, nitric oxide expression, and sequestration of tryptophan from rickettsiae are mechanisms by which rickettsiae are killed within cells. Direct contact of infected endothelial cells with perforin-producing CD8 T lymphocytes and interferon-γ–producing natural killer cells, accompanied by rickettsia antibody, helps control the infection. The timing and balance between rickettsia-mediated increases in vascular permeability and the benefits of induction of innate and adaptive immunity are likely the major determinants of severity and outcome.

Clinical Manifestations

The incubation period of RMSF in children varies from 2 to 14 days (median: 7 days). In 49% of cases, patients or their parents report a history of removing an attached tick, although the site of the tick bite is usually inapparent. Epidemiologic clues include living in or visiting an endemic area, playing or hiking in the woods, typical season, similar illness in family members, and close contact with a dog. In patients presenting for care, the illness is initially nonspecific, and most patients are not diagnosed during their first visit with a healthcare practitioner. Manifestations often (>50%) include fever, rash (frequently involving the palms or soles), nausea and vomiting, and headache, and less often (<50%) myalgias, abdominal pain, diarrhea, conjunctival injection, altered mental status, lymphadenopathy, and peripheral edema. Pain and tenderness of calf muscles are particularly common in children.

The typical clinical triad of fever, headache, and rash is observed in 58% of pediatric patients overall, and rash involving soles and palms first appearing after day 3 is associated with significantly higher risk of death among Mexican children. Fever and headache persist if the illness is untreated. Fever can exceed 40°C (104°F) and can remain persistently elevated or can fluctuate dramatically. Headache is severe, unremitting, and unresponsive to analgesics.

Rash usually appears after only 1-2 days of illness, and an estimated 3–5% of children never develop a rash that is recognized. Initially, discrete, pale, rose-red blanching macules or maculopapules appear; characteristically this initial rash is observed on the extremities, including the wrists, ankles, or lower legs ( Fig. 255.4 ). In 65% of patients, the initial rash spreads rapidly to involve the entire body, including the soles and palms. The rash can become petechial or even hemorrhagic, sometimes with palpable purpura.

In severe disease, the petechiae can enlarge into ecchymoses, which can become necrotic ( Fig. 255.5 ). Severe vascular obstruction secondary to the rickettsial vasculitis and thrombosis is uncommon but can result in gangrene of the digits, earlobes, scrotum, nose, or an entire limb.

Central nervous system infection usually manifests as changes in mental status (33%) or as photophobia (18%), seizure (17%), or meningismus (16%). Patients can also manifest ataxia, coma, or auditory deficits. Cerebrospinal fluid parameters are usually normal, but one-third have pleocytosis (<10-300 cells/µL), either mononuclear or less often neutrophil-dominated. Some (20%) have elevated protein (<200 mg/dL) in the cerebrospinal fluid; hypoglycorrhachia is rare. Neuroimaging studies often reveal only subtle abnormalities. However, with advanced disease and neurologic signs, a unique but nonspecific “starry sky” appearance may be observed on brain MRI that reflects the same systemic vasculitis observed with skin lesions.

Laboratory Findings

Laboratory abnormalities are common but nonspecific. Thrombocytopenia occurs in 60%, and the total white blood cell count is most often normal, with leukocytosis in 24% and leukopenia in 9%. Other characteristic abnormalities include a left-shifted leukocyte differential, anemia (33%), hyponatremia (<135 mEq/mL in 52%), and elevated serum aminotransferase levels (50%).

Diagnosis

Delays in diagnosis and treatment are associated with severe disease and death. Because no reliable diagnostic test is readily available to confirm RMSF during acute illness, the decision to treat must be based on compatible epidemiologic, clinical, and laboratory features. RMSF should be considered in patients presenting spring through fall with an acute febrile illness accompanied by headache and myalgia (particularly if they report exposure to ticks or contact with a dog or have been in forested or tick-infested rural areas). A history of tick exposure, a rash (especially if on the palms or soles), a normal or low leukocyte count with a marked left shift, a relatively low or decreasing platelet count, and a low serum sodium concentration are all clues that can support a diagnosis of RMSF. In patients without a rash or in dark-skinned patients in whom a rash can be difficult to appreciate, the diagnosis can be exceptionally elusive and delayed. One half of pediatric deaths occur within 9 days of onset of symptoms. Thus, treatment should not be withheld pending definitive laboratory results for a patient with clinically suspected illness. Further, prompt response to early treatment is diagnostically helpful.

If a rash is present, a vasculotropic rickettsial infection can be diagnosed as early as day 1 or 2 of illness with biopsy of a petechial lesion and immunohistochemical or immunofluorescent demonstration of specific rickettsial antigen in the endothelium. Although very specific, the sensitivity of this method is probably 70% at most. Furthermore, it can be adversely influenced by prior antimicrobial therapy, suboptimal selection of skin lesions for biopsy, and examination of insufficient tissue because of the focal nature of the infection. Tissue or blood can also be evaluated for R. rickettsii nucleic acids by polymerase chain reaction (PCR) at the CDC and selected public health or reference laboratories; PCR on blood is less sensitive than PCR on tissue and of similar sensitivity to tissue immunohistology, probably because the level of rickettsemia is generally very low (<6 rickettsiae/mL). Since eschars are rare with RMSF, scab scrapings or skin swabs are not useful specimens for the detection of rickettsemia by PCR.

Definitive diagnosis is most often accomplished by serology, which is retrospective, because a rise in titer is not seen until after the 1st wk of illness. The gold standard for the diagnosis of RMSF is a 4-fold increase in immunoglobulin G antibody titer by indirect fluorescent antibody assay between paired acute and convalescent (at 2-4 wk) sera or demonstration of seroconversion with a minimum convalescent titer higher than the positive cutoff (e.g., 128). A single titer is neither sensitive (patients can die before seroconversion) nor specific (an elevated titer can represent prior infection). Despite the historic role of IgM testing, its role in early diagnosis has recently become controversial and cannot be advocated. With current serologic methods, RMSF cannot be reliably distinguished from other spotted fever group rickettsiae infections. Cross reactions with typhus group rickettsiae also occur, but titers may be lower for the typhus group. Cross reactions are not seen with Ehrlichia or Anaplasma infections. Currently, ELISA serologic methods can only provide “probable” rather than confirmed evidence of infection. Weil-Felix antibody testing should not be performed, because it lacks both sensitivity and specificity. RMSF and other spotted fever group rickettsioses are reportable diseases in the United States.

Differential Diagnosis

Other rickettsial infections are easily confused with RMSF, especially all forms of human ehrlichiosis and murine typhus and novel spotted fever group rickettsioses that result from R. parkeri or “ R. philipii str. 364D” infections. RMSF can also mimic a variety of other diseases, such as meningococcemia and enteroviral infections. Negative blood cultures can exclude meningococcemia. PCR can differentiate enterovirus from R. rickettsii in patients with aseptic meningitis and cerebrospinal fluid pleocytosis. Other diseases in the differential diagnosis are typhoid fever, secondary syphilis, Lyme disease, leptospirosis, rat-bite fever, scarlet fever, toxic shock syndrome, rheumatic fever, rubella, parvovirus infection, Kawasaki disease, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, Henoch-Schönlein purpura, hemolytic uremic syndrome, aseptic meningitis, acute gastrointestinal illness, acute abdomen, hepatitis, infectious mononucleosis, hemophagocytic and macrophage activation syndromes, dengue fever, and drug reactions.