Abstract.
Scrub typhus is an acute febrile illness caused by the obligate intracellular organism Orientia tsutsugamushi, endemic to South Korea. The course of scrub typhus can range from a self-limiting disease to a fatal illness. Serological cross-reactivity has been reported with other intracellular organisms, including Rickettsia species, Chlamydophila species, and Mycoplasma pneumoniae. We conducted a retrospective study to assess the current seroprevalence of M. pneumoniae IgM and Chlamydia pneumoniae IgM in scrub typhus patients in South Korea. We enrolled 150 patients with suspected rickettsial disease over the course of 2 years. Of these patients, 60 were confirmed to have scrub typhus and had paired acute and convalescent serum. Among the 60 scrub typhus patients, 40 (66.7%) had M. pneumoniae IgM and 19 (31.7%) had C. pneumoniae IgM in acute- or convalescent phase sera. The seroconversion rates of M. pneumoniae IgG and IgM were 16.7% and 33.3%, respectively. The seroconversion rates of C. pneumoniae IgG and IgM were 8.3% and 11.7%, respectively. Compared with previous study results, this may indicate a relatively high seroprevalence of M. pneumoniae IgM and C. pneumoniae IgM in scrub typhus patients, indicating possible misdiagnosis of M. pneumoniae and C. pneumoniae infections in non-endemic scrub typhus areas.
INTRODUCTION
Scrub typhus is an acute febrile illness caused by the obligate intracellular organism Orientia tsutsugamushi, which is transmitted by the bites of infected chigger mites.1 Scrub typhus was previously thought to be geographically restricted to the Asia-Pacific “Tsutsugamushi triangle,” but recent evidence from the United Arab Emirates, Chile, and possibly Africa suggest a wider global distribution.2–5 The course of scrub typhus can range from a self-limiting disease to a fatal illness if not appropriately treated, with an estimated mortality of 6.0% (median, range 0–70.0%).6 Complications including pneumonia, acute respiratory distress syndrome, acute kidney injury, hepatitis, gastrointestinal bleeding, meningoencephalitis, myocarditis, and shock may occur.7
Mycoplasma pneumoniae and Chlamydia pneumoniae are the most common atypical pathogens that cause community-acquired pneumonia (CAP) worldwide.8 Mycoplasma pneumoniae accounts for 4–8% of all CAP cases and up to 20–40% of cases in the general population during epidemics.9 Mycoplasma pneumoniae can cause infections in all age groups, but older children and young adults are most frequently affected.10 Chlamydia pneumoniae, another agent associated with CAP, accounts for 6–20% of CAP cases.11 Clinical presentations of M. pneumoniae and C. pneumoniae infections vary. Indeed, they are well known for producing a wide range of extrapulmonary manifestations that can affect almost every organ of the body.12
In a recent study in Taiwan, 57.8% and 25.5% of acute Q fever cases were serum positive for M. pneumoniae IgM and C. pneumoniae IgM, respectively. For scrub typhus, these values were 7.7% and 28.2%, respectively, and for murine typhus, they were 0% and 42.9%, respectively.13 In Q fever patients, serological cross-reactivity has been reported with other intracellular pathogens, including Rickettsia species,14,15 Chlamydophila species,16,17 and M. pneumoniae,14 Bartonella species,18,19 and Legionella species.20,21 Therefore, there is a possibility that serum tests will produce a false-positive result for M. pneumoniae IgM and C. pneumoniae IgM in scrub typhus patients because of serological cross-reactivity. This means it is possible to misdiagnose scrub typhus as M. pneumoniae or C. pneumoniae infection. Because scrub typhus is widely endemic in rural areas of South Korea, we performed a retrospective study to assess the current seroprevalence of M. pneumoniae IgM and C. pneumoniae IgM among scrub typhus patients and to avoid misdiagnosis of scrub typhus.
METHODS
Patients and data collection.
A single-center retrospective study was conducted in a 1,200-bed tertiary hospital between January 2016 and December 2017. Patients 18 years of age and older who were suspected of having rickettsial disease were eligible. The initial blood specimens were obtained within 2 days of hospital admission, and follow-up blood specimens were acquired after appropriate treatment.
Demographic and clinical information were collected retrospectively from electronic medical records, including age, gender, comorbidities, clinical symptoms and signs, chest X-ray findings, and treatment.
Microbiological study.
Indirect immunofluorescence assay (IFA; sensitivity, 70–91%; specificity, 84–100%) is the current gold standard test for diagnosis of scrub typhus.22 ELISA is the most common diagnostic method of C. pneumoniae and M. pneumoniae because of the low cost and relatively high sensitivity and specificity.23 Chemiluminescence immunoassay (CLIA), an effective combination of immunoreaction and chemiluminescent system, has a high concordance with ELISA.24 Moreover, CLIA has a higher specificity and sensitivity for the detection of IgM (sensitivity, 65.8%; specificity, 100%) and IgG (sensitivity, 94.9%; specificity, 99.9%) and has been proposed for the clinical diagnosis of M. pneumoniae infection.25
In this study, the diagnosis of scrub typhus was confirmed by a ≥ 1:160 increase in an IFA titer against O. tsutsugamushi, a ≥ 4-fold increase in paired sera, or a positive result of nested polymerase chain reaction (PCR) targeting the 56-kDa antigen genes of O. tsutsugamushi. Acute- and convalescent-phase sera IgG and IgM antibodies against M. pneumoniae and C. pneumoniae were detected using CLIA (positive threshold ≥ 10.0 AU/mL) and ELISA (positive threshold > 11.0 AU/mL) at the Green Cross Reference Laboratory (Yongin, Korea). In addition, multiplex PCR was performed for the simultaneous detection of M. pneumoniae and C. pneumoniae as described previously by Corsaro et al.26
Statistical analysis.
Statistical analyses were performed with Student’s t-tests and χ2 tests or Fisher’s exact tests depending on the variable, using SPSS version 19 (IBM Corp., Armonk, NY). In all analyses, a two-tailed P-value of < 0.05 was considered significant.
Ethical statement.
This study was conducted in accordance with Good Clinical Practice Guidelines and the Declaration of Helsinki. The study was approved by the Institutional Review Board (IRB) of Chonbuk National University Hospital (IRB registration number 2018-11-029), and all patients provided written informed consent.
RESULTS
Over the study period, 150 patients were suspected of a rickettsial disease. Of the 85 confirmed scrub typhus patients, 60 had paired acute- and convalescent-phase serum and were included in this study, whereas samples could not be obtained from 25 patients.
Clinical characteristics of the 85 confirmed scrub typhus patients are as follows: fever (84, 98.8%), chills (59, 69.4%), headache (44, 51.8%), general weakness (64, 75.3%), myalgia (58, 68.2%), sore throat (14, 16.5%), cough (10, 11.8%), dyspnea (18, 21.1%), nausea or vomiting (24, 28.2%), abdominal pain or discomfort (19, 22.4%), lymphadenopathy (16, 18.8%), rash (64, 75.3%), and eschar (76, 89.4%).
The serum IgG and IgM results of M. pneumoniae and C. pneumoniae in the 60 patients are presented in Table 1. In acute- or convalescent-phase sera, 40 (66.7%) and 19 (31.7%) patients were positive for M. pneumoniae IgM and C. pneumoniae IgM, respectively. By contrast, the positivity rate of IgG was higher in C. pneumoniae (55 patients, 91.7%). The seroconversion rates of M. pneumoniae IgG/IgM (16.7% and 33.3%, respectively) were higher than those of C. pneumoniae IgG/IgM (8.3% and 11.7%, respectively) (Table 2). The results of PCR for M. pneumoniae and C. pneumoniae were all negative.
Table 1.
Results of available sera tests for Mycoplasma pneumoniae and Chlamydia pneumoniae IgM and IgG antibodies in scrub typhus patients
| Positive antibodies in the acute or convalescent phase | Scrub typhus (N = 60) |
|---|---|
| M. pneumoniae IgM, n (%) | |
| Acute or convalescent phase | 40 (66.7) |
| Acute phase | 20 (33.3) |
| Convalescent phase | 36 (60.0) |
| M. pneumoniae IgG, n (%) | |
| Acute or convalescent phase | 15 (25.0) |
| Acute phase | 5 (8.3) |
| Convalescent phase | 13 (21.7) |
| C. pneumoniae IgM, n (%) | |
| Acute or convalescent phase | 19 (31.7) |
| Acute phase | 12 (20.0) |
| Convalescent phase | 17 (28.3) |
| C. pneumoniae IgG, n (%) | |
| Acute or convalescent phase | 55 (91.7) |
| Acute phase | 50 (83.3) |
| Convalescent phase | 53 (88.3) |
Table 2.
Results of paired sera tests for Mycoplasma pneumoniae and Chlamydia pneumoniae IgM and IgG antibodies in scrub typhus patients
| Positive antibodies in the acute or convalescent phase | Scrub typhus (N = 60) |
|---|---|
| M. pneumoniae IgM, n (%) | |
| Seroconversion | 20 (33.3) |
| Seroreversion | 4 (6.7) |
| Both positive | 16 (26.7) |
| Both negative | 20 (33.3) |
| M. pneumoniae IgG, n (%) | |
| Seroconversion | 10 (16.7) |
| Seroreversion | 2 (3.3) |
| Both positive | 3 (5.0) |
| Both negative | 45 (75.0) |
| C. pneumoniae IgM, n (%) | |
| Seroconversion | 7 (11.7) |
| Seroreversion | 2 (3.3) |
| Both positive | 10 (16.7) |
| Both negative | 41 (68.3) |
| C. pneumoniae IgG, n (%) | |
| Seroconversion | 5 (8.3) |
| Seroreversion | 2 (3.3) |
| Both positive | 48 (80.0) |
| Both negative | 5 (8.3) |
Most scrub typhus patients who tested positive for M. pneumoniae IgM were aged between 50 and 79 years (Figure 1). Data from 2011 for pneumonia patients positive for M. pneumoniae in South Korea, however, indicate that those patients were generally young (Figure 1).
Figure 1.
Age distributions of scrub typhus patients with serum positivity for Mycoplasma pneumoniae IgM (comb pattern) and pneumonia patients with M. pneumoniae (filling).27
The demographic and clinical characteristics of the 60 enrolled patients are summarized in Table 3. There were no statistically significant differences among clinical symptoms and signs, imaging findings, or laboratory findings between the group that tested negative for M. pneumoniae IgM and the group that tested positive.
Table 3.
Demographic and clinical characteristics of scrub typhus patients with positive or negative Mycoplasma pneumoniae IgM results
| Characteristics | Negative for M. pneumoniae IgM (N = 20) | Positive for M. pneumoniae IgM (N = 40) | Total (N = 60) | P-value |
|---|---|---|---|---|
| Age (years), mean ± SD (range) | 65.50 ± 9.81 | 65.47 ± 14.85 | 65.48 ± 13.29 | 0.995 |
| Gender, n (%) | ||||
| Male | 8 (40.0) | 12 (30.0) | 20 (33.3) | 0.439 |
| Comorbidities, n (%) | ||||
| Cardiovascular disease* | 3 (15.0) | 3 (7.5) | 6 (10.0) | 0.361 |
| Cerebrovascular disease | 2 (10.0) | 7 (17.5) | 9 (15.0) | 0.443 |
| COPD | 0 | 0 | 0 | |
| Connective tissue disease | 0 | 1 (2.5) | 1 (1.7) | 0.476 |
| Liver disease | 0 | 1 (2.5) | 1 (1.7) | 0.476 |
| CKD | 0 | 0 | 0 | |
| DM | 8 (40.0) | 14 (35.0) | 22 (36.7) | 0.705 |
| Solid tumor | 1 (5.0) | 3 (7.5) | 4 (6.7) | 0.714 |
| Leukemia/lymphoma | 0 | 0 | 0 | |
| Clinical symptoms and signs, n (%) | ||||
| Fever | 20 (100.0) | 40 (100.0) | 60 (100.0) | |
| Chills | 13 (65.0) | 28 (70.0) | 41 (68.3) | 0.695 |
| Headache | 12 (60.0) | 20 (50.0) | 32 (53.3) | 0.464 |
| General weakness | 15 (75.0) | 29 (72.5) | 44 (73.3) | 0.836 |
| Myalgia | 17 (85.0) | 24 (60.0) | 41 (68.3) | 0.05 |
| Sore throat | 5 (25.0) | 5 (12.5) | 10 (16.7) | 0.221 |
| Cough | 3 (15.0) | 6 (15.0) | 9 (15.0) | 1 |
| Dyspnea | 3 (15.0) | 9 (22.5) | 12 (20.0) | 0.494 |
| Nausea or vomiting | 3 (15.0) | 13 (32.5) | 16 (26.7) | 0.148 |
| Abdominal pain or discomfort | 5 (25.0) | 8 (20.0) | 13 (21.7) | 0.658 |
| Lymphadenopathy | 6 (30.0) | 9 (22.5) | 15 (25.0 | 0.527 |
| Loss of appetite | 7 (35.0) | 18 (45.0) | 25 (41.7) | 0.459 |
| Rash | 16 (80.0) | 30 (75.0) | 46 (76.7) | 0.666 |
| Eschar | 18 (90.0) | 37 (92.5) | 55 (91.7) | 0.741 |
| Abnormal CXR findings | ||||
| Pneumonia | 1 (5.0) | 4 (10.0) | 5 (8.3) | 0.509 |
| Pulmonary edema | 4 (20.0) | 12 (30.0) | 16 (26.7) | 0.409 |
| Laboratory findings | ||||
| WBC (×103/mm3), mean ± SD | 7.00 ± 4.76 | 8.57 ± 3.56 | 8.08 ± 4.03 | 0.156 |
| Platelets (×103/mm3), mean ± SD | 130.00 ± 38.06 | 125.78 ± 51.97 | 128.52 ± 47.61 | 0.533 |
| AST (IU/L), mean ± SD | 111.00 ± 78.25 | 119.53 ± 90.49 | 116.68 ± 86.03 | 0.721 |
| ALT (IU/L), mean ± SD | 96.35 ± 86.24 | 94.40 ± 70.57 | 95.05 ± 75.42 | 0.926 |
| Total bilirubin (mg/dL), mean ± SD | 0.72 ± 0.46 | 0.83 ± 0.53 | 0.79 ± 0.51 | 0.445 |
| Creatinine (mg/dL), mean ± SD | 0.91 ± 0.80 | 0.94 ± 0.62 | 0.93 ± 0.68 | 0.893 |
| CRP (mg/L), mean ± SD | 82.53 ± 55.45 | 101.27 ± 58.20 | 95.0 ± 57.5 | 0.237 |
| Treatment | ||||
| Doxycycline | 14 (70.0) | 27 (67.5) | 41 (68.3) | 0.844 |
| Azithromycin | 0 | 4 (10.0) | 4 (3.7) | 0.143 |
| Azithromycin or doxycycline | 6 (30.0) | 9 (22.5) | 15 (25.0) | 0.527 |
COPD = chronic obstructive pulmonary disease; CKD = chronic kidney disease; DM = diabetes mellitus; CXR = chest X-ray; AST = aspartate aminotransferase; ALT = alanine aminotransferase; CRP = C-reactive protein.
* Includes myocardial infarction, congestive heart failure, and peripheral vascular disease.
DISCUSSION
In this study, 66.7% of scrub typhus cases were serum positive for M. pneumoniae IgM and 31.7% were positive for C. pneumoniae IgM. Whereas the positive rate for C. pneumoniae IgM in scrub typhus was comparable to data reported previously from Taiwan, the positive rate of M. pneumoniae IgM was much higher than previously reported (7.7%).13 These results could have clinical implications for misdiagnosis and overestimation of M. pneumoniae or C. pneumoniae infection.
We found obvious differences in the age distributions of scrub typhus patients positive for M. pneumoniae IgM and pneumonia patients positive for M. pneumoniae (Figure 1).27 We also report no differences in clinical symptoms and signs, imaging findings, or laboratory findings between the M. pneumoniae IgM–negative group and M. pneumoniae IgM–positive group (Table 3). The seropositivity and seroconversion of M. pneumoniae IgM and C. pneumoniae IgM imply a high probability of serological cross-reaction, and that true M. pneumoniae or C. pneumoniae infection is unlikely.
In recent years, there were two case reports about coinfection of O. tsutsugamushi and M. pneumoniae.28,29 One case was a 21-year-old woman with an eschar, cough, fever, and headache. Orientia tsutsugamushi was confirmed by real-time PCR, and M. pneumoniae was confirmed by serologic tests.29 The other case was a 12-year-old girl who presented with fever, rash, and an eschar. In that case, coinfection with O. tsutsugamushi, M. pneumoniae, and hepatitis B virus was confirmed by serologic tests. It is, however, easy to misinterpret the results as a M. pneumoniae infection rather than a coinfection.28 Therefore, clinicians should pay particular attention to diagnosis of coinfection of O. tsutsugamushi and M. pneumoniae or C. pneumoniae. In reference to the high seroprevalence of M. pneumoniae IgM and C. pneumoniae IgM in our study, these clinical situations can lead to overestimation of M. pneumoniae or C. pneumoniae infection in scrub typhus patients.
We are aware that this study is a single-center retrospective study that has limitations. The results should be interpreted with caution and should not be generalized to all patients. Still, we believe that the results have important clinical implications. Our seroprevalence study of M. pneumoniae IgM and C. pneumoniae IgM among scrub typhus patients in South Korea showed substantial rates of seropositivity of M. pneumoniae IgM and C. pneumoniae IgM in scrub typhus, suggesting high levels of serological cross-reactivity.
In conclusion, we report a high seroprevalence of M. pneumoniae IgM and C. pneumoniae IgM in scrub typhus patients. One important implication of our results is that misdiagnosis is possible in several situations: atypical CAP in scrub typhus non-endemic areas, cases when patients do not present an eschar or a rash in scrub typhus–endemic areas, and even in cases where patients present with fever of unknown origin or pneumonia. Therefore, we recommend caution when interpreting positive serological results for M. pneumoniae IgM and C. pneumoniae IgM in patients with scrub typhus.
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