A Case Series on Spotted Fever and Typhus Fever Seropositivity at National Center for Disease Control and Epidemiological Perspective

Abstract

Background:

The rickettsioses, except for typhus fever and scrub typhus (ST), were not really recognized as distinct clinical entities until the early 20th century. Only when specific rickettsial serologic testing was introduced in the 1940s could the precise etiologies of various rickettsial diseases (RDs) be determined with certainty. Although ST is a well- recognized zoonotic disease entity, but non-scrub typhus rickettsial infection like spotted fever group and typhus group are not well studied in India and are still underestimated.

Methods:

We report cases who had shown seropositivity of spotted fever and typhus fever RD in IgM and IgG ELISA whose samples were referred from various hospitals of Delhi/National Capital Region in which clinicians had strong suspicion of rickettsiosis other than ST or Weil—Felix test found positive for any of the OX2, 19, and K antigens.

Results:

We reported 18 cases of SFG and TGRD with mostly cases presented with fever followed by hepato-intestinal symptoms.

Conclusion:

The vast variability and nonspecific presentation of rickettsiosis in spotted and typhus fever at times have often made it difficult to diagnose clinically. Prompt antibiotic therapy shortens the course of the disease, lowers the risk of complications, and in turn, reduces morbidity and mortality owing to RDs. There is a distinct need for physicians and health care workers at all levels of care in India to be aware of the clinical features, available diagnostic tests and their interpretation, and the therapy for these infections.

Introduction

The rickettsioses, except for typhus fever group (TG) and scrub typhus group (STG), were not really recognized as distinct clinical entities until the early 20th century. Only when specific rickettsial serologic group testing was introduced in the 1940s could the precise etiologies of various rickettsial group diseases be determined and differentiated into spotted fever group (SFG), TG, or STG with limited certainty. However, in the SFG, serology cannot still differentiate infection by one species (e.g., Rickettsia conorii) from another (e.g., R. rickettsii) as antigen cross-reaction is so high. In the TG, serology cannot differentiate R. prowazekii infection from R. typhi infection, although the two diseases (epidemic typhus and murine typhus, respectively) are clinically very different.

The first authentic report of typhus fever in India came from Gooty in 1808 where 15 cases of typhus were admitted in His Majesty’s Hospital (Manual on zoonotic disease of public health importance, 2016). Thus, SFG and TG of rickettsial diseases (RDs) are one of the oldest, but recently recognized as important re-emerging disease often presenting as acute febrile illness (AFI). From the last two decades, RD is being reported from almost all parts of India (Rathi et al., 2011). However, the nonscrub typhus rickettsial infection like SFG and TG are not well studied in India and are still underestimated.

Table 1.

Socio-Demographic and Clinical Profile of Febrile Cases with Spotted and Typhus Fever Group Seropositivity

S. No	Age	Gender	Eschar	Rash	Clinical manifestations					Scrub typhus		Spotted fever		Rickettsia typhi		Weil–Felix test
S. No	Age	Gender	Eschar	Rash	Neurological	Hemorrhagic	Pulmonary	Hepatointestinal	Renal	IgM ELISA	IgG ELISA	IgM ELISA	IgG ELISA	IgM ELISA	IgG ELISA	OX2	OX19	OXK
1.	15	Female	Absent	Present	Present	Absent	Absent	Present	Absent	Negative	Not done	Negative	Negative	Negative	Positive	1:40	1:160	1:80
2.	28	Male	Absent	Absent	Absent	Absent	Absent	Present	Absent	Negative	Not done	Positive	Negative	Negative	Negative	1:20	<1:20	1:40
3.	6	Male	Absent	Present	Present	Absent	Absent	Present	Absent	Negative	Negative	Negative	Positive	Positive	Positive	1:80	1:20	1:160
4.	16	Female	Absent	Absent	Present	Absent	Absent	Present	Absent	Negative	Negative	Negative	Negative	Equivocal	Positive	1:40	<1:20	1:40
5.	30	Male	Absent	Absent	Present	Absent	Absent	Present	Absent	Negative	Negative	Positive	Negative	Negative	Negative	1:80	1:40	1:40
6.	19	Female	Absent	Absent	Present	Absent	Absent	Present	Present	Negative	Negative	Negative	Negative	Positive	Positive	1:40	<1:20	1:40
7.	2.5	Male	Present	Present	Absent	Absent	Absent	Absent	Absent	Negative	Negative	Negative	Positive	Equivocal	Positive	1:40	1:20	1:40
8.	12	Male	Absent	Absent	Absent	Present	Absent	Present	Absent	Negative	Not done	Positive	Negative	Negative	Negative	1:20	<1:20	1:80
9.	14	Male	Absent	Absent	Absent	Absent	Absent	Present	Absent	Negative	Negative	Negative	Negative	Negative	Positive	1:40	1:20	1:40
10.	12	Male	Absent	Absent	Present	Absent	Absent	Present	Absent	Negative	Not done	Positive	Negative	Negative	Negative	1:160	1:20	1:20
11.	4	Female	Absent	Absent	Absent	Absent	Absent	Present	Absent	Negative	Positive	Positive	Negative	Negative	Negative	1:40	<1:20	1:80
12.	6	Female	Absent	Absent	Present	Absent	Present	Present	Absent	Negative	Not done	Negative	Negative	Negative	Positive	1:20	<1:20	1:40
13.	16	Female	Absent	Absent	Absent	Absent	Absent	Present	Absent	Negative	Negative	Negative	Negative	Negative	Positive	1:160	<1:20	1:40
14.	8	Female	Absent	Absent	Present	Absent	Absent	Present	Absent	Negative	Negative	Positive	Negative	Negative	Negative	1:40	<1:20	1:80
15.	5	Female	Absent	Present	Absent	Absent	Absent	Present	Absent	Negative	Negative	Positive	Negative	Negative	Negative	1:160	<1:20	1:160
16.	30	Female	Absent	Absent	Present	Absent	Absent	Present	Present	Negative	Not done	Negative	Negative	Negative	Positive	1:40	<1:20	1:160
17.	16	Male	Present	Absent	Absent	Present	Present	Present	Present	Negative	Not done	Negative	Negative	Negative	Positive	1:40	<1:20	1:40
18.	50	Male	Absent	Absent	Present	Absent	Absent	Present	Absent	Negative	Not done	Negative	Negative	Negative	Positive	<1:20	<1:20	<1:20

Epidemiological studies in Jammu and Kashmir revealed that the earlier epidemics of 1927 and 1942–43 were caused by R. prowazekii (Hussain, 1945). A similar outbreak during 1947–48 among the refugees of Jammu and Kashmir led to the isolation of five strains—three from humans and two from lice pools (Kalra and Rao, 1951). Hence, historical evidence suggests that louse-borne typhus fever caused by R. prowazekii is a recognized cause of typhus fever.

Serological evidence about the presence of tick typhus in India was provided (Topping et al., 1943) where the sera from three suspected cases from Mysore were sent to the National Institute of Health, Bethesda, USA, where CF tests performed indicated that the causative agent had a close immunological relationship to R. rickettsii (Topping et al., 1943). However, in India, Indian tick typhus caused by R. conorii, which is a member of SFG is a recognized cause for SFG illness.

Case Description

We report cases who had shown seropositivity of SFG and TG RD and whose samples were referred from various hospitals of Delhi/National Capital Region in which clinician had strong suspicion of rickettsiosis other than ST or Weil–Felix test (WFT) was found positive (≥1:80 titer) for any of the OX2, 19, and K antigens. IgM and IgG were detected for SFG and TG by enzyme immune assay (EIA; Fuller Laboratories, California, USA). The antigens utilized in TG rickettsia EIA IgM kit were recombinant outer membrane protein (rOmp B) purified from R. typhi and in TG rickettsia EIA IgG were rOmp B and lipopolysaccharide (LPS) antigen purified from R. typhi. SFG rickettsia EIA IgM kit utilized rOmp A and rOmp B contained both species specific and more broadly reactive determinants purified from R. rickettsii and SFG rickettsia EIA IgG kit utilized a group specific LPS (r LPS) extracted from SFG rickettisia species including R. rickettsia, R. conorii, R. siberica, R. australis, and R. akari. Interpretation of results was done as per the kit literature. A cutoff calibrator is provided in the kit for discrimination between reactive and nonreactive sera.

Socio-demographic profile and clinical presentation in patients with suspected rickettsiosis found seropositive for typhus fever and SFG by IgM/IgG ELISA were studied. Seropositivity in IgM ELISA was considered as recent infection and seropositivity in IgG ELISA was considered as past infection/exposure.

Discussion

Rickettsial infection has a wide spectrum of disease. In most patients, it is mild; but serious complications and fatalities have also been reported if not treated on time (Parola et al., 2005: Mahajan, 2012). Establishing the etiological diagnosis is important and has to be differentiated from diseases with similar presentation like atypical measles, dengue, malaria, sepsis, meningococcemia, leptospirosis, and vasculitis syndromes. Physicians should rule out clinically and by laboratory investigations examination of paired serum samples for serological evidence. Many cases of rickettsial infection are believed to go undiagnosed owing to lack of diagnostic facilities (Mahajan, 2012; Parola et al., 2005). Most widely used laboratory assay to diagnose the RD is ELISA. Indirect immunofluorescence antibody (IFA) assays using paired acute and convalescent sera are the reference standard for serologic confirmation of rickettsial infection but rarely performed owing to cost implications and trained manpower. The confirmation of specific RDs should not be made using the sole criterion of the positivity in the nonspecific WFT and must be clinically correlated along with ELISA for specific rickettsiosis diagnosis. Further, WFT can be a screening test, which may give clue for ST and other rickettsiosis in resource-limited settings.

Few studies reported the prevalence of the SFG in a range of 1.8–7.7% for IgM and 0.3–15.3% for IgG depending on the patient type included in the studies and setting (outbreak or endemic) (Khan et al., 2021; Mane et al., 2019). A study from South India reported 10.4% and 8.4% seroprevalence of IgG for SFG and TG rickettsioses, respectively (Devamani et al., 2020). Mittal et al. (2012) reported 39.3% positivity for SFG and 8.1% positivity for TG on the basis of WFT. The IgG response is inconsistent and, may be, owing to past infection (50%) or less-pronounced infection in SFG whereas repeated infections in other RDs, the increased level of IgG is seen, which could be the reason for underestimation of prevalence of SFG (Schmidt et al., 2021). However, from the diagnostic point of view, most of the labs perform IgG detection for both SFG and TG (Parola et al., 2005; Schmidt et al., 2021). The detection of IgG antibodies is considered more accurate than IgM in TG rickettsioses. The detectable level of IgG antibodies appears after 7–10 days after the onset of illness. There are less serological data on TG.

Epidemiological studies in Jammu and Kashmir revealed that the earlier epidemics of 1927 in Gujjars in Singhapore pass with a few fatal cases suffering from suppurative parotitis and that of 1942–43 in the Himalayan belt were caused by R. prowazekii. A total of 146 blood specimens of suspected typhus cases were examined, out of which 67 showed agglutination with OX19, 6 with OXK, and none with OX2 (Hussain, 1945). Recently, six samples of Central Reserve Police Force commandos from 2017, who were posted in a dense forest of Chhattisgarh, had been tested for TG (IgM ELISA, Fuller Laboratories, California, USA). They had presented with symptoms of fever with or without encephalopathy and all were found positive at our center (Unpublished data). In recent years, studies from many parts from the country like Maharashtra, Tamil Nadu, North-East states, Chhattisgarh, Delhi, and Uttar Pradesh have reported the typhus fever cases (Devamani et al., 2020; Parola et al., 2005).

Megaw received personal communications about the presence of spotted fever (tick typhus) in Nagpur, Hyderabad, Kanpur, and Saugar (Megaw, 1917). With the passage of time, cases were also reported from Allahabad, Narsapatnam, Ratlam, Secunderabad, Trichinapally, Bangalore, Jhansi, Nainital, Darjeeling, Pune, and Lucknow. Outbreaks of louse-borne typhus have been restricted entirely along the northern frontier of the country, however, Wright, in 1883, described outbreaks in Saugor and Jabalpur (Madhya Pradesh) in the past and that they have also been reported in Chhattisgarh and other parts of country in recent times. He had described that cases were recently common in spring and early autumn, which classically resemble typhus as found in Europe except the rash that may be obscured by dark skin of natives of India (Rice, 1883).

The incidence of these diseases has been reported more in pediatric population with high suspicion of RD. Murali et al. (2001) found positivity of 7% and 10.5% for SFG and TG, respectively, in pediatric group. In Gorakhpur, 70% prevalence of the SFG was recorded in the pediatric age group (Mane et al., 2019). Studies from Tamil Nadu also reported prevalence of 1.1% and 7.8% of SFG and TG, respectively, in children who presented with pyrexia of unknown origin (PUO) (Somashekhar et al., 2006). Khan et al. (2021) found the highest SFG followed by ST and TG burden in a study in North-East India. In the present study, the positivity rates of both SFG and TG were more in age group <16 years as compared with other age groups, comprising 80% of the total positive cases.

In our cases, fever followed by hepatointestinal manifestations and neurological manifestations were the most commonly associated clinical features with both the diseases of SFG and TG. In other studies, these manifestations have been documented in a range of 10–80% and 2–40%, respectively (Gautam et al., 2019; Kalal et al., 2016; Somashekhar et al., 2006). Most of the studies on RD have focused on the patients with AFI and PUO. After fever, rash was found to be the most common clinical manifestation associated with SFG and TG in various studies where rash with fever was the inclusion criteria. However, eschar, which is a classical finding of the RD, was not frequently associated. Our finding also showed renal, hemorrhagic, and pulmonary manifestations.

In our study, there are three cases that had shown the copositivity in more than one RD—one case was found positive for IgG SFG and IgG TG, one was found positive for IgG ST and IgM SFG, and one was found positive for IgM TG, IgG TG, and IgG SFG. Proper IFA serology with titres on paired serum sample may be needed to clarify the cross-reactivity or coinfection in such cases. There are few limitations in the study. First, the molecular tests for SF, TG, and ST rickettsioses could not be done because for the molecular testing, the appropriate samples are to be withdrawn within 10 days of illness and without starting antibiotic course. Second, ST IgG ELISA was not done for 8 out of 18 cases owing to kit unavailability. Third, we were not able to do paired sera sample testing.

Conclusion

The vast variability and nonspecific presentation of rickettsiosis even in spotted and typhus fever at times have often made it difficult to diagnose clinically. Prompt antibiotic therapy shortens the course of the disease, lowers the risk of complications, and in turn, reduces morbidity and mortality owing to RDs. There is a distinct need for physicians and health care workers at all levels of care in India to be aware of the clinical features, available diagnostic tests and their interpretation, and the therapy of these infections. The reasons for underreporting of such diseases may be (1) difficulty in diagnosis owing to nonspecific sign and symptoms, (2) limited availability and expensive diagnostic tests, and (3) lack of awareness among health care providers especially in rural areas. Misdiagnosis and underreporting of RD lead to extensive investigations in patients with fever of unknown origin and often patients land up in complications. Further, lack of suspicion and timely management leads to extra financial burden on patients and also poses the patient on risk of antimicrobial resistance because of irrational use of the antimicrobial agents prescribed for PUO.

Footnotes

Acknowledgments

We acknowledge the contributions of Ms Neeru Kakkar, Assistant Research Officer, NCDC, and Mr Charanjeet Singh, Research Assistant, NCDC.

Authors’ Contributions

S.G. and C.S.: Writing—original draft. V.S., P.S., J.K., and S.S.: Data curation. M.S.: Conceptualization and writing—review and editing.

Authors Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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