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ORIGINAL ARTICLE
Year : 2019  |  Volume : 7  |  Issue : 4  |  Page : 120-126

A comparative study of concurrent infections of rickettsial infection, Malaria, Typhoid, and Chikungunya with Dengue


Department of Medicine, MVJ MC and RH, Bengaluru, Karnataka, India

Date of Submission08-Jun-2019
Date of Acceptance04-Sep-2019
Date of Web Publication18-Oct-2019

Correspondence Address:
Dr. Vasantha Kamath
MVJ MC and RH, Dandupalya, National Highway 4, 30th Km Milestone, Kolathur P.O., Hoskote, Bengaluru - 562 114, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AJIM.AJIM_3_19

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  Abstract 

Introduction: In endemic countries such as India, the possibility that acute febrile illnesses are caused due to multiple infectious etiologies is not a rarity. In the postmonsoon season, dengue may often co-exist in the same patient concurrently with other infections such as scrub typhus, chikungunya, malaria, and typhoid. Materials and Methods: This is a prospective observational study aiming to understand the clinical and laboratory parameters and complications of concurrent infections such as typhoid, malaria, rickettsial infection, or chikungunya with dengue. Results: A total of 420 cases of dengue mono-infections were noted. Ninety-two of 512 patients with dengue were co-infected. The most common co-infection was dengue with rickettsiae (48.8%) followed by typhoid (22.2%). Rural, young, males were most affected by co-infections in contrast to mono-infections where rural and urban distribution is similar. The incidence of significant bleed increased in cases of malaria with dengue. Musculoskeletal, gastrointestinal, cardiac, and respiratory complications were seen in increased frequency in co-infections cases. Two deaths were noted in the co-infected groups of rickettsial diseases. Conclusion: The clinical picture and management of co-infected patients differ substantially from patients with mono-infections of dengue. Prompt recognition is necessary to allow the initiation of appropriate intervention in a timely manner. This excludes the possibility of increased morbidity and mortality, which is often avoidable.

Keywords: Chikungunya, dengue concurrent infection, malaria, rickettsial infection, typhoid


How to cite this article:
Kamath V, Ganguly S, Avinash B L. A comparative study of concurrent infections of rickettsial infection, Malaria, Typhoid, and Chikungunya with Dengue. APIK J Int Med 2019;7:120-6

How to cite this URL:
Kamath V, Ganguly S, Avinash B L. A comparative study of concurrent infections of rickettsial infection, Malaria, Typhoid, and Chikungunya with Dengue. APIK J Int Med [serial online] 2019 [cited 2019 Dec 6];7:120-6. Available from: http://www.ajim.in/text.asp?2019/7/4/120/269563




  Introduction Top


Acute febrile illness (AFI) is a ubiquitous syndrome among patients seeking hospital care in India. Infections remain the most common cause for AFI in this tropical country. Seasonal variation of prevalent infections is a well-established norm. Dengue, rickettsial infection, malaria, typhoid, and leptospira are widely distributed. These are the common causes of AFI.

During the seasonal increase in dengue cases (especially during or early postmonsoon when temperatures range from 26°C to 30°C), there is a possibility of concurrent infections with other infectious agents. In the endemic areas, concomitant infections can often cause diagnostic problems. Common clinical features, modalities of presentation, and laboratory findings can be muddled and modulated by the effects of infections occurring concurrently in a single host. This may befuddle a clinician, especially in resource-challenged setups, where it may not be possible to confirm the clinical suspicion of multiple infections.

The epidemiology, disease course, and complications of dengue co-infection have been studied in many parts of the country. Dengue fever is spread by Aedes mosquito and is caused by four viral serotypes, i.e., dengue virus-1, 2, 3, and 4. Infections range from asymptomatic or mild clinical features to life-threatening complications such as dengue hemorrhagic fever (DHF) and dengue shock syndrome. Chikungunya virus (CHIKV) is also transmitted by Aedes mosquito, causing chikungunya. CHIKV has three distinct evolutionary classes – African, West African, and Central or East African.[1] Rickettsial infections are caused by Rickettsiae. These are a heterogeneous group of small, obligately, intracellular, Gram-negative coccobacilli and short bacilli, most of which are transmitted by a tick, mite, flea, or louse vector. It often presents in a similar manner to dengue. However, concurrent rickettsial infection with dengue makes for an interesting study because the infections have two different vectors involved. Previous studies by this author have shown scrub typhus caused by Orientia tsutsugamushi to be the most prevalent form of rickettsial infections in the area subserved by the hospital under study.[2] Malaria is a protozoal parasitic infection caused by the Plasmodium species. It is transmitted by Anopheles mosquito. In endemic areas, with increased rates of vectors, the two infections often co-exist.[3] Typhoid fever caused by  Salmonella More Details typhi is transmitted by the feco–oral route. However, in both developed and developing countries, they have been known to occur concurrently in hosts. Leptospirosis is a zoonotic disease caused by spirochaetes. The clinical manifestations can range from mild asymptomatic infection to severe hemorrhagic manifestations.

Unlike a mono-infection, the treatment regimens for co-infections are not the same. A balance of risks, complications, and efficacy often precludes a cautious and judicious approach toward care. Significantly, a delay in implementing appropriate treatment due to failure or poor diagnosis can lead to fatalities in such situations.[1]

This study aims to review the geographic limits, the distinguishing clinical features, the laboratory parameters, and the epidemiological patterns of their co-distribution. This should increase the awareness and understanding of these co-infections and aid astute clinicians in their decision-making and patient management.


  Materials and Methods Top


This is a prospective, observational study done from June 2017 to January 2019 in the Medicine Department of MVJ MC and RH, Bengaluru. Karnataka, India. All cases of AFIs were screened for dengue, rickettsial fever, typhoid, malaria, chikungunya, and Leptospirosis. This was done through a detailed history, clinical examination, and laboratory investigations. Dengue was diagnosed by serology with nonstructural protein 1 antigen and immunoglobulin (Ig) M capture enzyme-linked immunosorbent assay (ELISA) test. Rickettsial fever was diagnosed by Weil–Felix test (a 4-fold rise in the agglutinin titers 2–4 weeks apart or a single-titer dilution more than 1:320 was considered significant in appropriate clinical setting). Serodiagnosis of typhoid was by Widal test (single acute-phase sample with O >1:160 and H >1:160 or rising titer). Chikungunya was diagnosed with CHIKV positive serology. Leptospirosis was diagnosed by utilizing Leptospira IgM capture ELISA as part of the modified Faine's diagnostic criteria for the diagnosis of Leptospira cases in India.[4] Malaria was diagnosed with thick and thin smears and rapid card test. All seropositive cases of dengue with co-infection were considered for the study. Descriptive statistics were used to analyze and present the findings from the study.


  Results Top


A total of 778 patients of AFI were admitted during the study period. A total of 512 cases tested positive for dengue. Rickettsial fever was diagnosed in 125 patients, typhoid was found in 32, malaria was found in 22, and chikungunya was found in 20 patients. Dengue with co-infection was present in 92 patients [Figure 1]. None of the patients were diagnosed with Leptospirosis and hence the disease is excluded from subsequent discussion.
Figure 1: Causes of acute febrile thrombocytopenia

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In our study, most of the cases of co-infection are from rural area (75.5%) residing in Kolar (Mulbagal, Sidlagatta, and Shrinivaspur) (59.9%) and Chinthamani (41.1%) [Figure 2]. This is contrast to dengue mono-infections which showed an equal predilection for urban and rural population. In the co-infected group, the majority of the cases are farmer by occupation. The cases were seen in lower and middle socioeconomic classes (74.4%). Age group involved was 20–30 years of age. Males (62.2%) were affected more than females (37.8%), with a male-to-female ratio of 1.64:1.
Figure 2: Area of co-infection with dengue (shaded black)

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Clinical presentation of dengue with co-infection

All patients with dengue mono-infection presented with fever. Nearly 82% of them had myalgia, and 47.8% of patients also had arthralgia. Pain abdomen was seen in 25% of the patients and vomiting in 32.7% of the patients. Approximately 6% of patients presented with symptoms suggestive of a bleeding manifestation. Decreased urine output was a common presenting feature, attributing to 4.6% of cases. The rest of the symptoms were seen in less number of cases [Table 1].
Table 1: Clinical features (symptoms) of dengue co-infections with rickettsial, typhoid, malaria, and chikungunya virus infections

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When compared to mono-infections, patients having dengue with rickettsial fever had similar occurrence of myalgia (84%) and arthralgia (40.9%). However, they presented with increased frequency of cough (9%, P = 0.012) and breathlessness (9%, P = 0.01). On examination, 84% of cases had icterus (P = 0.02) and 63.6% had hepatomegaly (P = 0.03). Eschar was seen only in 6.8% and 32% of the patients had bleeding manifestations, which was similar to dengue mono-infection (32.6%, P = 1.2). The examination findings are elucidated in [Table 2].
Table 2: Clinical features (signs) of dengue co-infections with rickettsial, typhoid, malaria, and chikungunya virus infections

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Dengue with typhoid co-infection predominantly presented with gastrointestinal symptoms of pain abdomen (90%, P = 0.01), loose stools (70%, P = 0.03), and vomiting (45%, P = 0.042). Half of the patients were found to have bradycardia compared to only 20% of patients with dengue mono-infection (P = 0.023). Bleeding manifestations were not seen in this group of co-infections.

All patients of dengue with malaria had high-grade fever (100%). Bleeding manifestations were common (66.6%, P = 0.014), along with severe myalgia (86.6%). Greater instance of oliguria was seen (6.6%, P = 0.05). On examination, most of them had hepatosplenomegaly (P = 0.02), along with proximal muscle swelling and tenderness. Both mucosal and skin bleed (66%, P = 0.015) were seen.

Patients with chikungunya co-infection presented with fever (100%), severe arthralgia (100%), restriction of joint movement, and swelling of joint. The latter two features were not seen in the mono-infection group. Most of the patients had arthritis of both large and small joints with marked tenderness and swelling.

The detailed clinical findings are summarized in [Table 1] and [Table 2].

Laboratory parameters seen in co-infection

In comparison to mono-infections, most of the patients having dengue with rickettsial infection had increased transaminitis (77%, P = 0.03) and altered renal parameters (26%, P = 0.04). However, they had similar levels of thrombocytopenia (84%) and gall bladder wall edema (22.7%).

Patients having dengue with typhoid had electrolyte abnormality (patients had hypokalemia 40%, no cases of hyponatremia). This was statistically significantly greater than the incidence of electrolyte abnormalities seen in dengue mono-infection (16.4%, P = 0.012) along with transaminitis (P = 0.04).

Most of the patients having dengue with malaria had severe thrombocytopenia (90%) and transaminitis (72%), and creatine phosphokinase (CPK) was raised in 72% of patients, suggesting myositis (P < 0.01).

Dengue with chikungunya patients had raised erythrocyte sedimentation rate (ESR) (100%), and 18.8% of the patients had raised CPK levels (P < 0.01). There was no instance of raised ESR in mono-infection cases.

The findings are summarized in [Table 3].
Table 3: Laboratory features of dengue co-infections with rickettsial, typhoid, malaria, and chikungunya virus infections

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Complications

  1. Bleeding – Patients having dengue with malaria had severe bleeding manifestations requiring management as per the dengue haemorrhagic fever (DHF) guidelines followed by dengue with rickettsial group of infections. The level of thrombocytopenia was directly related to the extent of bleeding seen in these co-infections. However, the threshold for bleeding with malaria was more erratic [Table 4]
  2. Respiratory – Three patients having dengue with rickettsial co-infection who presented with cough and breathlessness progressed to develop acute respiratory distress syndrome (ARDS) [Figure 3] and required mechanical ventilation and other supportive measures
  3. Myositis – Two patients having dengue with malaria co-infection had severe muscles tenderness and swelling of proximal muscles of the lower limb and were found to have significant raised CPK enzymes; one further progressed into rhabdomyolysis (raised urine myoglobin) and later developed acute kidney injury (AKI)
  4. Myocarditis – Three patients having dengue with rickettsial group of infection were found to have hypotension, significant ST-T segment changes, prolonged QT interval, and raised levels of CPK- muscle/brain
  5. Mortality – Two patients having dengue with rickettsial infection and one patient having dengue with malarial infection succumbed to death due to ARDS and multiple organ dysfunction syndrome (MODS) respectively
  6. Duration of stay in hospital – Patients with co-infection had a longer duration of stay (10 days) and required vigilant monitoring and aggressive treatment compared to the average duration of stay with dengue mono-infection (~5 days)
  7. AKI – Patients with dengue mono-infection posited the largest group of patients developing AKI. This was only followed by cases of dengue with malaria, where too the incidence of AKI was large [Table 2].
Figure 3: Chest X-ray showing acute respiratory distress syndrome picture

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Table 4: Levels of platelet count at which symptomatic bleed is seen in dengue co-infections

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  Discussion Top


Dengue fever is endemic in most parts of South-East Asia with outbreaks in and around rainy season. Concurrent infections with multiple pathogens in the same individual are not uncommon in developing countries. Co-infections of dengue with chikungunya, malaria, and other arboviruses have been frequently reported from endemic areas. We did not have any cases of Leptospirosis so that, it was excluded from analysis and discussion.

Many studies have shown co-infection of dengue with rickettsial, typhoid, chikungunya, and malaria. None of the study had correlated all these four co-infections with their clinical manifestation and complications. To our knowledge, this is the first study of this kind.

In our study, 92 patients had co-infections. The most common co-infection was dengue with rickettsiae (48.8%) followed by typhoid (22.2%). The most common age group involved was between 20 and 30 years of age (48.8%), similar to the study by Basheer et al. in co-infection of dengue with scrub typhus.[5]

Our study showed a slight male preponderance. Most of our patients belonged to rural background (75.5%) compared to urban (24.5%). This is perhaps explained by the greater number of hours spent by young men out in the agricultural fields.

In the present study, all patients with rickettsial co-infection had high-grade fever, which was also seen in a study done by Saleem et al.[6] Rash, which is the hallmark of rickettsial infections, is not seen in all cases and nor seen at presentation.[2] In the current study, 45.45% of patients had rash. Eschar, which is pathognomonic, was seen only in 3.5% of patients.[6] This correlates with our study of 6.8%. Nearly 66.8% of our patients had hepatomegaly and 77% had transaminitis. This is a feature well described in literature, and elevated transaminases have also been described in both dengue fever and scrub typhus.[2],[6] Almost 84% of the patients had thrombocytopenia. Thrombocytopenia in both infections is believed to be immune mediated; hence, co-infected patients probably had synergistic immune suppression of platelets, leading to lower platelet counts.[6],[7] Almost 13.63% of patients had hypoproteinemia, and 4.5% out of 13.63% had leukocytosis. These patients did not have eschar at presentation and had severe thrombocytopenia requiring multiple platelet transfusions and had a longer duration of stay in the hospital. In the present study, 9% of patients presented with cough at presentation progressed to ARDS requiring ventilatory support. Nearly 6.81% of patients had myocarditis. Similar figures have been reported by Garg et al.[8] and Saleem et al.[6]

The exact incidence of dengue with typhoid co-infection is not known. Both dengue and typhoid occur seasonally in India, especially during monsoon season. Increased feco–oral transmission and the breeding of mosquitoes in stagnant water can lead to enhanced chances of co-infection. The inflammatory and hemodynamic changes occurring in dengue infection can predispose to invasive Salmonella infection.[9] In our study, patients having dengue with typhoid fever presented predominantly with gastrointestinal symptoms of pain abdomen, loose stools, and vomiting. None of the patients had bleeding manifestations, which was also seen in a study by Sharma et al.[9] and Ramya et al.[10] Nearly 60% of the patients had icterus and 68% of the patients had transaminitis, which can be explained both in dengue and typhoid fever. There is a dearth of literature regarding dengue–typhoid co-infection, the possible effect that one disease can have progression/regression of the other, and the gravity of complications if both co-exist or whether one disease precedes the other.

Many cases of dengue with malarial co-infection have been reported from many parts of the world. Carme et al. from France have reported multiple such cases in 2009.[11] Documented evidence of dengue with malarial co-infection is rare in Asia, but there is evidence of clinical severity when compared to mono-infection. In our study, all patients had high-grade fever, and 66.6% of the patients had icterus, which can be due to active hemolysis and hepatic involvement seen in both dengue and malaria. Nearly 66.6% of patients presented with bleeding manifestations and 90% of patients had thrombocytopenia, and the degree of thrombocytopenia did not correlate to the clinically significant bleeding, which was also reported in a study done by Magalhães et al.[12] In our study, 72% of patients had transaminitis and 26.6% had anemia, which was also reported in a study done by Mendonça et al.[13]

Almost 86.6% of patients in our study had myalgia and 13.3% of patients had weakness, swelling, and tenderness of thigh and calf muscles, features suggestive of myositis. It was backed up by raised CPK levels seen in 73.3% of the patients, which can be due to both dengue and malaria or their synergistic effect. The postulated mechanism of myositis in malaria is tumor necrosis factor-alpha, increased blood viscosity, sequestration of red blood cell in the muscle, metabolic toxins released by parasites, and lactic acidosis which can cause myositis, myonecrosis, and myoglobinuria.[14] Postulated mechanisms in dengue are muscle edema, hemorrhage, metabolic alterations, and changes in vascular endothelial cells, which are responsible for muscular dysfunction in dengue myositis. Cytokines, such as tumor necrosis factor, released during the viremia, lead to intense inflammation and subsequent damage to muscle fibers.[15]

In our study, 6.6% of patients had severe muscle tenderness, very high CPK levels (24,000), and decreased urine output at presentation. On evaluation, they were found to have AKI and myoglobinuria requiring emergency dialysis and further progressed to MODS, which was also reported by Yong et al.[16]

The mechanism of AKI is multifactorial, and these factors include various inflammatory mediators, intravascular hemolysis and coagulation, hypovolemia from dehydration, hyperparasitemia, and immune complexes.[16]

All patients of dengue with chikungunya presented with fever, arthralgia, and myalgia. Nearly 90.9% of patients had early morning stiffness, 54.5% had restriction of joint movement, and 36.3% had swelling of joints involving both small and large joints, which are consistent with the study done by Londhey et al.[17] In our study, all patients had raised ESR, and this co-infection group had the least incidence of thrombocytopenia and complications compared to other co-infection groups.

Limitations of the study

Dengue serotyping was not done. It would have given an idea about which serotype was commonly involved in co-infection and virulence expressed by each type of serotype in co-infection. The overlap of clinical syndrome seen in co-infection could not be determined as to which infection predominantly played a role or a synergistic effect was seen. Cultures, other microbial assays, and polymerase chain reaction were not employed as they were unacceptable as screening tests. Speciation of rickettsial infections and malaria was not utilized for analysis as the small sample size for comparison would bias the conclusions.


  Conclusion Top


Co-infection should always be considered in endemic areas. A high degree of suspicion for co-infections must be present in patients presenting with febrile illness in tropics, especially, while dealing with patients with AFI in postmonsoon season with multisystem involvement. Co-infections have multiple overlapping clinical symptoms which often make it difficult to identify them clinically. Patients should be screened for co-infections when feasible. This will help in initiating appropriate treatment and reduce the increased morbidity and mortality which is usually avoidable. Larger prospective studies are required to estimate the exact magnitude and impact this co-infection.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Singh J, Dinkar A, Singh RG, Siddiqui MS, Sinha N, Singh SK, et al. Clinical profile of dengue fever and coinfection with chikungunya. Ci Ji Yi Xue Za Zhi 2018;30:158-64.  Back to cited text no. 1
    
2.
Kamath V, Ganguly S, Bhatia JK. Rickettsial infections: Spreading beyond boundaries. In: Narsimalu G, editor. Progress in Medicine. Vol. 29. Mumbai: Jaypee; 2019. p. 195-9.  Back to cited text no. 2
    
3.
Salam N, Mustafa S, Hafiz A, Chaudhary AA, Deeba F, Parveen S. Global prevalence and distribution of coinfection of malaria, dengue and chikungunya: A systematic review. BMC Public Health 2018;18:710.  Back to cited text no. 3
    
4.
Kumar SS. Indian guidelines for the diagnosis and management of human leptospirosis. In: Medicine Update 2013. Mumbai: Jaypee; 2013. p. 23-9.  Back to cited text no. 4
    
5.
Basheer A, Iqbal N, Mookkappan S, Anitha P, Nair S, Kanungo R, et al. Clinical and laboratory characteristics of dengue-orientia tsutsugamushi co-infection from a tertiary care center in South India. Mediterr J Hematol Infect Dis 2016;8:e2016028.  Back to cited text no. 5
    
6.
Saleem M, Gopal R, Shivekar SS, Mangaiyarkarasi T. Scrub typhus & dengue co-infection among patients attending a tertiary care hospital at Puducherry. Indian J Microbiol Res 2016;3:149.  Back to cited text no. 6
    
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Sapkota S, Bhandari S, Sapkota S, Hamal R. Dengue and scrub typhus coinfection in a patient presenting with febrile illness. Case Rep Infect Dis 2017;2017:6214083.  Back to cited text no. 7
    
8.
Garg A, Jain A, Kashyap R. Travel-acquired scrub typhus infection masked by dengue fever in a patient from nonendemic area. J Glob Infect Dis 2018;10:114-5.  Back to cited text no. 8
    
9.
Sharma Y, Arya V, Jain S, Kumar M, Deka L, Mathur A. Dengue and typhoid co-infection- study from a government hospital in North Delhi. J Clin Diagn Res 2014;8:DC09-11.  Back to cited text no. 9
    
10.
Ramya TG, Sunitha BR. Enteric fever cases showing concurrent seropositivity with Dengue and malaria: A sero-diagnostic challenge. Microbiol Res 2018;8:69-72.  Back to cited text no. 10
    
11.
Carme B, Matheus S, Donutil G, Raulin O, Nacher M, Morvan J. Concurrent dengue and malaria in Cayenne hospital, French Guiana. Emerg Infect Dis 2009;15:668-71.  Back to cited text no. 11
    
12.
Magalhães BM, Siqueira AM, Alexandre MA, Souza MS, Gimaque JB, Bastos MS, et al. P. Vivax malaria and dengue fever co-infection: A cross-sectional study in the Brazilian amazon. PLoS Negl Trop Dis 2014;8:e3239.  Back to cited text no. 12
    
13.
Mendonça VR, Andrade BB, Souza LC, Magalhães BM, Mourão MP, Lacerda MV, et al. Unravelling the patterns of host immune responses in Plasmodium vivax malaria and dengue co-infection. Malar J 2015;14:315.  Back to cited text no. 13
    
14.
Swash M, Schwartz MS. Malaria myositis. J Neurol Neurosurg Psychiatry 1993;56:1328.  Back to cited text no. 14
    
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Garg RK, Malhotra HS, Jain A, Malhotra KP. Dengue-associated neuromuscular complications. Neurol India 2015;63:497-516.  Back to cited text no. 15
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16.
Yong KP, Tan BH, Low CY. Severe falciparum malaria with dengue coinfection complicated by rhabdomyolysis and acute kidney injury: An unusual case with myoglobinemia, myoglobinuria but normal serum creatine kinase. BMC Infect Dis 2012;12:364.  Back to cited text no. 16
    
17.
Londhey V, Agrawal S, Vaidya N, Kini S, Shastri JS, Sunil S. Dengue and Chikungunya virus co-infections: The inside story. J Assoc Physicians India 2016;64:36-40.  Back to cited text no. 17
    


    Figures

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    Tables

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