|Year : 2020 | Volume
| Issue : 1 | Page : 4-10
Rickettsial infections: Past and present perspectives
Vasantha Kamath, Shreyashi Ganguly, Jasmine Kaur Bhatia, R Himabindu
Department of Internal Medicine, MVJ Medical College and Research Hospital, Bengaluru, Karnataka, India
|Date of Submission||24-Jun-2019|
|Date of Decision||22-Jul-2019|
|Date of Acceptance||24-Sep-2019|
|Date of Web Publication||14-Jan-2020|
Dr. Vasantha Kamath
Dandupaya, 30th KM Milestone, National Highway 4, Kolathur PO, Hoskote, Bangalore - 562 114, Karnataka
Source of Support: None, Conflict of Interest: None
Rickettsial infections are reported from various parts of India. But despite the surging number of cases, these diseases are often under-diagnosed. Rickettsial diseases have re-emerged as some of the most covert infections of the present time. These diseases are generally incapacitating and notoriously difficult to diagnose. The greatest challenge lies in overcoming the difficult diagnostic dilemma posed by these infections early in their courses- when antibiotic therapy is most effective. Untreated cases have a fatality of up to 30% but when promptly and properly diagnosed, it is often easily treated. Clinical manifestations combined with a thorough history (travel, epidemiological environment, and place of residence) and knowledge of the distribution of rickettsial agents and their vectors may help clinicians to correctly diagnose a rickettsiosis. Weil Felix, although not sensitive, aids in initiating antibiotics when interpreted in the correct clinical context. Antibiotic treatment with doxycycline (including for children) must be started whenever a possible rickettsiosis is suspected, taking into consideration pregnant women and allergic patients. The factors that predispose to rickettsial infections are widely prevalent in this country hence the physicians and paediatricians need to include rickettsial infections in their differential diagnosis of febrile thrombocytopaenia or an acute febrile illness.
Keywords: Doxycycline, rickettsial infection, rickettsioses, scrub typhus, Weil–Felix
|How to cite this article:|
Kamath V, Ganguly S, Bhatia JK, Himabindu R. Rickettsial infections: Past and present perspectives. APIK J Int Med 2020;8:4-10
|How to cite this URL:|
Kamath V, Ganguly S, Bhatia JK, Himabindu R. Rickettsial infections: Past and present perspectives. APIK J Int Med [serial online] 2020 [cited 2022 Jul 6];8:4-10. Available from: https://www.ajim.in/text.asp?2020/8/1/4/275976
| Introduction|| |
Rickettsial diseases have reemerged as some of the most baneful insidious infections of the present time. The rickettsial diseases are generally incapacitating and notoriously difficult to diagnose. Untreated cases have a fatality of up to 30% but when promptly and properly diagnosed, it is often easily treated. The greatest challenge lies in overcoming the difficult diagnostic dilemma posed by these infections early in their courses, when antibiotic therapy is most effective.
Rickettsial infections are reported from various parts of India. However, despite the surging number of cases, these diseases are often underdiagnosed. The factors that predispose to rickettsial infections are widely prevalent in this country, hence the physicians and pediatricians need to include rickettsial infections in their differential diagnosis of febrile thrombocytopenia or an acute febrile illness.
| Rickettsia|| |
Rickettsia is obligately intracellular, small, nonflagellate, bacilli/coccobacillary forms with a Gram-negative cell wall that has inner and outer membranes separated by a periplasmic layer. Rickettsiae reside free in the cytosol and replicate by binary fission.
They are visualized using Giemsa (stains red) [Figure 1], Machiavello, and Gimenez staining or using direct fluorescent antibody staining techniques.
Owing to reductive evolution, rickettsiae have small genomes (1.1–1.5 Mb) housed in a single circular chromosome. These genomes contain split genes, gene remnants, and pseudogenes that, owing to the colinearity of some rickettsial genomes, may represent different steps of the genome degradation process. Genomics reveals extreme genome reduction and massive gene loss in highly vertebrate pathogenic Rickettsia compared to less virulent or endosymbiotic species.
The genome is geared toward obligate intracellular life, as characterized by:
- Lack of enzymes for sugar metabolism, lipid biosynthesis, nucleotide synthesis, and amino acid metabolism
- Enzymes for the complete tricarboxylic acid cycle and several copies of ATP/ADP translocase genes
- Type IV secretion system.
All rickettsiae share two outer membrane proteins (OmpB and Sca 4) and LPS biosynthesis machinery. RickA, unique to spotted fever rickettsiae, plays a role in the induction of actin polymerization [Figure 2]. The genomes also contain membranolytic, autotransporter, and adhesion genes.
|Figure 2: Rickettsial proteins aiding in internalization and pathogenesis|
Click here to view
Information gleaned from rickettsial genomics challenges traditional concepts of pathogenesis that focused primarily on the acquisition of virulence factors. Another intriguing phenomenon about the reduced rickettsial genomes concerns the large fraction of noncoding DNA and possible functionality of these “noncoding” sequences, because of the high conservation of these regions. Despite genome streamlining, Rickettsia spp. contains gene families, selfish DNA, repeat palindromic elements, and genes encoding eukaryotic-like motifs. These features participate in sequence and functional diversity and may play a crucial role in adaptation to the host cell and pathogenesis. Genome analyses have identified a large fraction of mobile genetic elements, including plasmids, suggesting the possibility of lateral gene transfer in these intracellular bacteria.
| The Rickettsiaceae Family|| |
Family Rickettsiaceae is divided into four genera, based on the lipopolysaccharide group antigen [Figure 3]. The former members that are no longer part of the Rickettsiaceae family are Coxiella burnetii (not primarily arthropod-borne causes Q fever) and Bartonella quintana (not an obligate intracellular parasite causes trench fever).
Rickettsiae are maintained in reservoir hosts (primarily rodents) and the alimentary tract of their hemophagocytic arthropod vectors [Figure 4]. The lifecycle of these microorganisms is determined by their survival in small mammals (which can act as reservoirs or as amplifiers) and in arthropods, such as ticks, fleas, lice, and mites, which can also act as vectors. Humans are accidental hosts (exception Rickettsia prowazekii).
Humans are infected as the vector defecates while feeding (the flea feeding reflex). The feces contaminate the bite wounds. The salivary secretions at bite site can also contaminate. They are not transmissible person to person, except by blood transfusion or organ transplantation.
In the case of R. prowazekii, close personal contact with a person having the infected louse, propagates the infection further.
The global distribution of rickettsial organisms is determined by its arthropod host/vector. Infections with tick vectors have a restricted geographic mapping and show remarkable endemicity. This is perhaps due to the mammalian population that the ticks prefer. Infections with other vectors have worldwide prevalence. Rickettsial diseases are, therefore, found everywhere, except in Antarctica.
| Pathogenesis|| |
Principal target cells are endothelial cells (exception Rickettsia akari). They induce cellular damage leading to detachment of cells. The circulating cells become the source of infection once they lodge in distal capillaries. Rickettsia may also enter phagocytic cells by antibody-mediated opsonization.
Rickettsial ompB binds specifically to Ku70, a component of the DNA-dependent protein kinase. The binding and recruitment of Ku70 to the plasma membrane are important events in the entry of Rickettsiae into nonphagocytic mammalian cells. This leads to the activation of a cascade of signaling events that are known to be strongly associated with β1-integrin activation and bacterial entry.
Most of the clinical characteristics of rickettsial diseases are attributed to disseminated infection of the endothelium, where they grow and stimulate oxidative stress, thereby causing injury to the endothelial cells.
The most prominent pathophysiological effects of rickettsial infection of endothelial cells include an increase in vascular permeability, generalized vascular inflammation, edema, increased leukocyte – endothelium interactions, and release of powerful vasoactive mediators that promote coagulation and proinflammatory cytokines.
The production of proinflammatory cytokines, such as interleukin (IL)-1α, Il-6, and Il-8, by endothelial cells promotes the expression of endothelial-cell adhesion molecules, which support the recruitment of T-cells to the site of infection. Rickettsiae also enhance the expression of chemokines, by infected endothelial cells.
The peak of expression of these chemokines correlates with maximal T-cell infiltration (mainly CD8 + T-cells) at the site of infection. However, it is not yet clear, whether greater chemokine production and increased T-cell migration to the site of infection contribute more to the pathogenesis of a severe disease or to protection against rickettsial infection.
| History of Rickettsioses|| |
Rickettsial infections represent some of the oldest and most devastating ailments known to humans. They have appeared time and again as the scourge of humans flourishing as epidemics during times of war and famine.
The first discovery of a Rickettsia was achieved by Howard Ricketts in the Bitterroot Valley of Montana in 1906 when he isolated the organisms from the blood of patients by inoculation of guinea pigs, which developed a febrile illness with distinctive scrotal swelling and hemorrhagic necrosis. He also visualized the organisms and detected them in ticks, a model elucidation of an emerging infectious disease.
Von Prowazek and da Rochalima in Europe and Ricketts in Mexico identified the causative agent of louse-borne typhus by feeding clean lice on infected patients, observing the development of rickettsial infection in the louse gut, infecting monkeys, and observing the organisms microscopically. This scientific tour de force resulted in the deaths of the investigators from infection with the agent named in their honor, R. prowazekii Of the prominent rickettsiologists [Figure 5], only Charles Nicolle survived to collect the Nobel prize for his work on epidemic typhus.
|Figure 5: The famous rickettsiologist - stanislaus Von Prowazek, Howard Taylor Ricketts, and Charles Nicolle with collaborators Helen Sparrow and Rudolph Weigl|
Click here to view
While early identification of new species was based on hazards and chance, the advent of polymerase chain reaction (PCR) and genomic fingerprinting have resulted in rapid escalation in the number of Rickettsial species identified and attributed to human diseases.
| Indian Context|| |
Rickettsial infection was initially seen in epidemic form during World War II. In 1965, and 1990, it resurged. These infections disappeared with the widespread use of insecticides to control vectors and use of tetracyclines as the first-line antibiotics by practitioners.
However, with the declining indiscriminate use of tetracyclines and the urbanization of rural areas have coincided with rickettsia's reemergence. Rickettsial strains with reduced susceptibility to antibiotics and surprising interactions with HIV have also been described.
Unfortunately, lack of awareness about the reemergence, and nonspecific presentation of the diseases lead to low index of suspicion. This results in underdiagnosis and higher mortality.
Eleven outbreaks have been reported from 2000 to 2011, with >900 cases and 42 deaths (case-fatality ratio 5%–17%) in Himachal Pradesh, Manipur, and one each from Jammu to Kashmir, Tamil Nadu, Pondicherry, West Bengal, and Meghalaya. Scrub typhus caused all the outbreaks (exception Kangra: epidemic typhus). Cases have also been reported from Rajasthan, Uttaranchal, Assam, Maharashtra, Kerala, and Karnataka.
| Risk Factors|| |
Rickettsiaceae are found in areas with sandy beaches, scrub vegetation, mountains, and equatorial rain forests. Factors increasing the risk of infections pertain to the exposure to the vectors. Living close to bushes, working in farms, cutting grass, urinating or defecating in bushy areas, infrequent bathing or changing clothes, and raising domestic animals are important contributors to the risk of infection.
| Clinical Features|| |
The incubation period is 2–21 days. It presents with nonspecific signs and symptoms mimicking a benign viral illness. The clinical features of Rickettsia were as follows:
- Fever, high grade, starts abruptly, associated with frontal headache, and generalized myalgia (lumbar region, thigh, and calves)
- Apathy, drowsiness, photophobia, and conjunctival suffusion 
- Generalized lymphadenopathy in the abdominopelvic, paraaortic, porta hepatis, and splenic hilum 
- Hepatosplenomegaly may also be seen.
Although considered the hallmark of rickettsial infection, it is neither seen at presentation nor in all patients. It develops 3–5 days after the onset of symptoms, maybe macular, maculopapular, petechial, or hemorrhagic. It characteristically seen over the palms and soles but also over the ankles, legs, and wrist. Pink, discrete blanching occurs over the trunk and extremities [Figure 6]. The petechiae are ecchymotic with necrosis of the digits, scrotum, nose, and ear lobes; may turn gangrenous.
An eschar is pathognomonic (7%–97%) but can be found in only 50% patients; in the axilla, groin, genitalia, chest, abdomen, or neck. At the site of bite, a vesicule/papule develops that ulcerates. It heals with the development of a black eschar with regional lymphadenopathy. The necrotic eschar has an erythematous edge [Figure 7].
Atypical presentations were as follows:
- Acute abdomen in the absence of fever
- Nausea, vomiting, and diarrhea in patients from hyperendemic areas
- Constipation in epidemic typhus.
Systemic presentations/complications were as follows:
- Encephalitis, aseptic meningitis, and meningoencephalitis
- Cough associated with pneumonia, acute respiratory distress syndrome
- Nausea, vomiting, abdominal pain, diarrhea, hepatitis, and acute hepatic failure
- Acute renal failure
Inflammation and vascular leakage lead to interstitial pneumonitis/noncardiogenic pulmonary edema (in 30%–60%), cerebral edema, and meningoencephalitis.
Coagulation factor consumption, platelet adhesion, and leucocyte emigration result in a disseminated intravascular coagulation-like syndrome.
In endemic areas, rickettsial meningoencephalitis must be included in the differential diagnosis of aseptic meningitis when associated with altered renal or liver function tests (LFT), jaundice, or acute renal failure.
Acute renal failure is associated with a poor prognosis.
Retinal vasculitis-asymptomatic in the early stage, commonly seen among females, resolves by 6 months and associated with a favorable prognosis.
Since rickettsial infections show specific geographical distributions, a syndromic approach may be applied to make a presumptive diagnosis of the causative organisms. The ones elucidated in [Table 1] pertain to India.
Patients with uncomplicated fever may recover within 2 weeks even without treatment. Complicated infection has a 30% mortality rate.
R. prowazekii is the only pathogen among various Rickettsial species with the acknowledged capacity to maintain persistent subclinical infection in convalescent patients, which can later manifest as recrudescent typhus or Brill–Zinsser disease.
Indicators of grave prognosis include
- Extremes of age
- Absence of an eschar/rash (more virulent strains have a lesser incidence of rash and eschar)
- Elevated TC >10,000 cells/mm 3
- Serum albumin <3 g/dl
- Associated comorbidities (diabetes or acute renal failure)
- Altered LFT
- Severe thrombocytopenia
- Severe/focal neurological signs.
| Investigations|| |
- Early stages lymphopenia; late stages lymphocytosis - 30%.
- Elevated erythrocyte sedimentation rate
- Thrombocytopenia (50%)
- Deranged LFT (50%): increased serum bilirubin, transaminitis (75%–95%), and decreased albumin (50%)
- Altered renal function
- Chest X-ray: pneumonitis, bilateral infiltrates, and pleural effusion
- Ultrasound abdomen: hepatosplenomegaly.
| Diagnosis|| |
Early in the course, the symptoms are nonspecific and pose a diagnostic dilemma. During this time, Weil–Felix test, which is readily available, can help in the early initiation of therapy when interpreted in the correct clinical context. Other antibody-based serological tests, aid in diagnosis only 5–7 days after onset.
Weil–Felix test is easily available, cheap, and easy to perform. The results are available overnight. Its sensitivity is 46%, specificity 100%. By the 2nd week, 50% were positive. Agglutinins from OX2, OX19, and OXK strains of Proteus bacteria are used. A four-fold rise in the agglutinin titers 2–4 weeks apart, or a single titer dilution >1:320 is considered positive. In some patients, antibodies persist for years after the original exposure. Therefore, results must be interpreted in the correct clinical context [Table 2]. Two sequential serum and plasma samples showing rising antibody level indicates an acute infection.
Indirect immunofluorescence assay/immunoperoxidase assay
It is the gold standard investigation with a sensitivity of 89%–100% and specificity of 99%–100%. However, it is not easily available, is expensive and takes more than 1 week for results to be available. IgM increases at the end of the 1st week; IgG at the end of the 2nd week. Positive IgM, with four-fold rise in the antibody titer, indicates a recent infection.
Useful during the acute phase of infection. Immunohistologic examination of a 3-mm cutaneous punch biopsy sample from a rash or a lymph node is 70% sensitive and 100% specific. It needs high expertise for interpretation.
Polymerase chain reaction
It is positive in the 1st week and is species-specific. It can be done on the whole blood, eschar, or skin biopsy. PCR has a specificity of 100%. Sensitivity for standard PCR is 22%–36%. It is 45%–82% for reverse transcription-PCR. The sensitivity is higher for tissue than blood sample.
The organism is grown on antibiotic-free eukaryotic cell-culture monolayer; median time for culture positivity being 27 days. Isolation of the organism requires a biosafety level III laboratory.
| Treatment|| |
Doxycycline is the drug of choice, dose 100 mg twice a day for 7–10 days. A prompt response occurs within 24–48 h in the form of disappearance of fever. Dramatic clinical improvement with rapid defervescence, is the norm. Lack of response within 48 h warrants search for different etiology.
Severely ill patients (especially with multiple organ dysfunction syndrome [MODS]) may require 10–14 days, before clinical improvement is noted. Treatment for less than a week is initially curative but may be followed by relapse.
Side effects are discoloration of teeth, hypoplasia of the enamel, depression of skeletal growth in children, and limb hypoplasia.
Doxycycline is contraindicated in children <8 years and pregnant women, instead azithromycin 500 mg once a day is used.
In case of poor response to doxycycline or drug-resistant serotypes: combination of azithromycin with rifampicin (600 mg once a day) or doxycycline with rifampicin for 6–8 days. Rifampicin is not used alone; may lead to the development of resistant strains.
Chloramphenicol may also be tried. Dose: 500 mg 6th h for 7–14 days in adults (children 150 mg/kg/day for 5 days). It may cause gray baby syndrome and bone marrow suppression.
When to hospitalize?
Treatment with doxycycline is often rewarding and most patients when treated early recover without incident. However, certain groups require inpatient care to reduce the morbidity and mortality.
Patients who require hospitalization are those in whom:
- Oral therapy is ineffective or not tolerated
- Presence of gastrointestinal symptoms such as severe nausea and vomiting
- MODS, thrombocytopenia, or altered mental status.
Supportive therapy is needed in the critically ill patients as iatrogenic cerebral, and pulmonary edema is easily precipitated (preexisting microvascular leakage).
The enormous antigenic variation among the rickettsial biogroups hampers efforts to produce an effective vaccine.
Even though Rickettsiae are intracellular parasites and that cellular adaptive immunity is critical during a primary infection, there is clear evidence that the humoral immune response is very important in preventing the development of disease during secondary infections or after a lethal challenge following passive serum transfer.
Inactivated vaccines for Rickettsia rickettsii and R. prowazekii were produced early from a variety of sources including their vectors but they were very reactogenic and protection was incomplete. Later on, inactivated vaccines were produced from Rickettsia cultivated in eggs, but antigenicity was variable and protection was poor.
In the 1950s, a very effective vaccine for epidemic typhus was produced. It was an attenuated strain denominated Madrid E; however, spontaneous reversion to a virulent phenotype precluded further development and testing.
Recent efforts have focused on the production of a subunit vaccine. Fragments of rickettsial proteins that may trigger protective immunity were tested. They include rOmpA and rOmpB, and results were encouraging. However, these approaches are limited and biased because of their focus on proteins that elicit a strong humoral response.
A major effort for identification of immunogenic antigens is clearly needed, and the antigen discovery effort will need new tools to identify relevant conserved antigens recognized by T-cells. At present, no vaccine is commercially available.
| Prevention|| |
In the absence of vaccines, prevention becomes the core of defensive strategies against these diseases. They rely on measures averting the vector bite. These include:
- Avoiding exposure to a vector-infested habitat
- Wearing closed-toed shoes
- Long pants, long-sleeved clothes treated with permethrin
- 20%–50% diethyltoluamide topical application
- Use of insect repellents
- Pets protected and checked regularly for ticks.
| Recent Developments|| |
Rickettsia has abundant surface outer membrane protein B (Oomp B). Antibodies to this protein could be a novel treatment target in the future.
| Conclusion|| |
In the last two decades, the characterization and involvement of Rickettsia as etiological agents of human diseases have increased considerably in India. In the early stages, these diseases pose a difficult diagnostic dilemma. Clinical manifestations combined with a thorough history (travel, epidemiological environment, and place of residence) and knowledge of the distribution of Rickettsial agents and their vectors may help clinicians to correctly diagnose a rickettsiosis.
The aim of this review was to provide physicians with a diagnostic approach, considering the common signs and symptoms of these diseases. Nevertheless, to achieve a definitive diagnosis, microbiological assays are needed.
Weil–Felix, although not sensitive, aids in initiating antibiotics when interpreted in the correct clinical context. Antibiotic treatment with doxycycline (including for children) must be started whenever a possible rickettsiosis is suspected, taking into consideration pregnant women and allergic patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Walker DH, Yu XJ. Progress in rickettsial genome analysis from pioneering of Rickettsia
prowazekii to the recent Rickettsia typhi
. Ann N Y Acad Sci 2005;1063:13-25.
Merhej V, Raoult D. Rickettsial evolution in the light of comparative genomics. Biol Rev Camb Philos Soc 2011;86:379-405.
Kelly DJ, Richards AL, Temenak J, Strickman D, Dasch GA. The past and present threat of rickettsial diseases to military medicine and international public health. Clin Infect Dis 2002;34:S145-69.
Fang R, Blanton LS, Walker DH. Rickettsiae as emerging infectious agents. Clin Lab Med 2017;37:383-400.
Walker DH, Ismail N. Emerging and re-emerging rickettsioses: Endothelial cell infection and early disease events. Nat Rev Microbiol 2008;6:375-86.
Walker DH. Rickettsiae and rickettsial infections: The current state of knowledge. Clin Infect Dis 2007;45 Suppl 1:S39-44.
Jiang J, Richards AL. Scrub typhus: No longer restricted to the tsutsugamushi triangle. Trop Med Infect Dis 2018;3: pii: E11.
Cowan G. Rickettsial diseases: The typhus group of fevers – A review. Postgrad Med J 2000;76:269-72.
Sirisanthana V, Puthanakit T, Sirisanthana T. Epidemiologic, clinical and laboratory features of scrub typhus in thirty Thai children. Pediatr Infect Dis J 2003;22:341-5.
Sanjay M. Rickettsial diseases. J Assoc Physicians India 2016;60:37-44.
Faccini-Martínez ÁA, García-Álvarez L, Hidalgo M, Oteo JA. Syndromic classification of rickettsioses: An approach for clinical practice. Int J Infect Dis 2014;28:126-39.
Luce-Fedrow A, Mullins K, Kostik AP, St John HK, Jiang J, Richards AL. Strategies for detecting rickettsiae and diagnosing rickettsial diseases. Future Microbiol 2015;10:537-64.
van Eekeren LE, de Vries SG, Wagenaar JF, Spijker R, Grobusch MP, Goorhuis A. Under-diagnosis of rickettsial disease in clinical practice: A systematic review. Travel Med Infect Dis 2018;26:7-15.
Lochary ME, Lockhart PB, Williams WT Jr. Doxycycline and staining of permanent teeth. Pediatr Infect Dis J 1998;17:429-31.
Rathi N, Rathi A. Rickettsial infections: Indian perspective. Indian Pediatr 2010;47:157-64.
Minahan NT, Chao CC, Tsai KH. The re-emergence and emergence of vector-borne rickettsioses in Taiwan. Trop Med Infect Dis 2017;3: pii: E1.
Valbueno G. Rickettsioses: Pathogenesis, immunity, and Vaccine Development. Acta Med Costarric 2013;55 Suppl 1:48-59.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2]