|Year : 2022 | Volume
| Issue : 5 | Page : 63-76
Expert group opinion for endemic bacterial infections in South Asia in solid organ transplant recipients - Typhoid, paratyphoid, leptospirosis, scrub typhus, and melioidosis
Vikas Deswal1, Venktasubramanian Ramasubramanian2, Abhyudaysingh Rana3, Shyam Bihari Bansal3, Sandeep Mahajan4
1 Department of Internal Medicine, Medanta - The Medicity, Gurugram, Haryana, India
2 Department of Infectious Diseases and Tropical Medicine, Apollo Hospitals, Chennai, Tamil Nadu, India
3 Department of Nephrology and Renal Transplant Medicine, Medanta Kidney and Urology Institute, Medanta - The Medicity, Gurugram, Haryana, India
4 Department of Nephrology, All India institute of Medical Sciences, New Delhi, India
|Date of Submission||05-Jan-2022|
|Date of Decision||08-Mar-2022|
|Date of Acceptance||10-Mar-2022|
|Date of Web Publication||18-Oct-2022|
Dr. Vikas Deswal
Department of Internal Medicine, Medanta - The Medicity, Sector 38, Gurugram - 122 001, Haryana
Source of Support: None, Conflict of Interest: None
Typhoid, paratyphoid, leptospirosis, scrub typhus, and melioidosis are some of the common bacterial infections which are endemic in the region of South Asia. Typhoid and paratyphoid cause enteric fever which is a common cause of fever in the general population in this region. It is caused by Salmonella through contaminated food and water. Enteric fever is one of the most common causes of fever in travelers in this region. Leptospirosis is a zoonotic disease caused by Leptospira and occurs due to direct contact with animals like or through abraded skin after the monsoon in the endemic area. Fever and jaundice are the most common presentations. Scrub typhus is caused by mite Orientia tsutsugamushi and it has now emerged as one of the most common causes of pyrexia in this region. Melioidosis is an uncommon infection caused by the bacteria Burkholderia pseudomalle, which is endemic in some regions of South Asia and is usually seen in immunocompromised individuals. Melioidosis is often called great mimicker due to a variety of clinical manifestations which might confuse it with other diseases. All these infections can cause fever or other systemic complications involving various organs in transplant recipients, so they should be kept as part of differential diagnosis of pyrexia in transplant recipients. There are no recommendations to screen for these infections in transplant candidates or donors, however, transplant candidates or donors with fever should be investigated for these infections and transplant should be deferred until full recovery and for some time thereafter.
Keywords: Bacterial, endemic, Leptospira, melioidosis, scrub typhus, South Asia, transplant, typhoid
|How to cite this article:|
Deswal V, Ramasubramanian V, Rana A, Bansal SB, Mahajan S. Expert group opinion for endemic bacterial infections in South Asia in solid organ transplant recipients - Typhoid, paratyphoid, leptospirosis, scrub typhus, and melioidosis. Indian J Transplant 2022;16, Suppl S1:63-76
|How to cite this URL:|
Deswal V, Ramasubramanian V, Rana A, Bansal SB, Mahajan S. Expert group opinion for endemic bacterial infections in South Asia in solid organ transplant recipients - Typhoid, paratyphoid, leptospirosis, scrub typhus, and melioidosis. Indian J Transplant [serial online] 2022 [cited 2022 Nov 27];16, Suppl S1:63-76. Available from: https://www.ijtonline.in/text.asp?2022/16/5/63/358662
| Melioidosis|| |
| Introduction|| |
Melioidosis is a tropical infection caused by the facultative Gram-negative bacterium and Burkholderia pseudomallei. It is an environmental saprophyte present in soil and fresh water in endemic regions.
| Epidemiology|| |
Melioidosis is mainly confined to areas of Southeast Asia, India, Northern Australia, and parts of China. North-Eastern Thailand and parts of Northern Australia are hyperendemic for melioidosis. Cases of melioidosis have been reported from outside endemic zones also. The majority of these cases are acquired by a visit to endemic areas, with symptoms arising later following departure from the endemic area.
In India, majority of cases are reported from coastal states of Karnataka and Tamil Nadu.
The majority of cases in all the endemic areas, namely Northern Australia, Thailand, and India, are seen in the rainy season.
Transmission of infection can occur through percutaneous inoculation, inhalation, aspiration, and occasionally ingestion. The predominant mode of transmission is percutaneous inoculation followed by bacterial seeding during exposure to wet season soils or contaminated water. During natural calamities such as storms, cyclone the mode of transmission will shift from inoculation to inhalation. Despite the huge burden of bacterial load in a critically ill patient with septicemic melioidosis, person-to-person transmission is extremely rare.
| Risk Factors|| |
The important risk factors for melioidosis are diabetes mellitus (especially poorly controlled), chronic lung disease, chronic kidney disease (CKD), and alcohol abuse. Other risk factors include thalassemia, sickle cell disease, and glucocorticoids use., Among the risk factors, diabetes appears to be the most common risk factor in various studies from India, Thailand, and Australia.,,,,,
Cases have also been reported in patients with pulmonary hemosiderosis, cystic fibrosis, rheumatic heart disease, congestive cardiac failure, and chronic granulomatous disease. In a large series of 540 patients from Australia, 6% of patients were receiving immunosuppressive therapy and few had some immune compromising condition.
| Chronic Kidney Disease and Melioidosis|| |
The causative agent of melioidosis, B. pseudomallei, is a facultative intracellular pathogen and in a milieu of CKD, neutrophils display impaired chemotaxis, reduced phagocytic ability, decreased generation of reactive oxygen intermediates during oxidative burst, and reduction in adenosine triphosphate., This probably explains the increased risk of melioidosis in patients with CKD.
| Time Course of Infection|| |
Serologic studies suggest that most infections with B. pseudomallei are asymptomatic, and severe clinical disease occurs mainly in those with risk factors.
| Incubation Period|| |
The incubation period of an acute infection ranges from 1 to 21 days (average 9 days). A more severe form of the disease with a shorter incubation period can occur after inhalation or aspiration of contaminated freshwater.
Inoculating dose of an organism, mode of transmission, host risk factors, and variable virulence properties of the isolate are the likely factors affecting the incubation period, clinical presentation, and outcomes.,
Symptomatic period <2 months.
Symptomatic period >2 months.
Infection with B. pseudomallei can be latent and subsequently reactivated. A latency period of as long as 29 years have been reported in the literature. In the famous Darwin study from Australia, only 4% of cases were due to the reactivation of B. pseudomallei from latent focus.
| Clinical Features|| |
Melioidosis has a wide variety of clinical manifestations which can mimic many other diseases and is often called “The great mimicker.”
The majority of cases in all the endemic areas, namely Northern Australia, Thailand, and India, are seen in the rainy season with the vast majority of them presenting as acute infection.,,,
Pneumonitis is one of the most common reported presentations in various studies from endemic areas across the world including South-East Asia.,,,, It is mostly seen in acute melioidosis and is associated with bacteremic illness.,,,, Bacteremia on presentation is seen in up to 55%–60% of cases in series from both India and Australia and is associated with higher mortality., The presence of septic shock is a strong predictor of mortality.
In India, acute melioidosis was a more common presentation in a series from western Karnataka, whereas chronic melioidosis is more common presentation in a series from Tamil Nadu.,
Visceral abscesses involving the liver, spleen, kidney, and prostate are well recognized.,, In a series from southern India, visceral abscesses (spleen and prostate) were more commonly seen with chronic melioidosis. Few case series have reported brain abscesses which probably occurred secondary to bacteremic seeding.,,
Genitourinary melioidosis presents with fever and suprapubic pain, dysuria, or acute retention of urine. The prostate was the most common site of involvement followed by kidneys, bladder, and seminal vesicles.
Parotitis is a common presentation in children, accounting up to 40% of cases in Thailand and Cambodia, whereas it is an uncommon presentation in both India and Australia.,,,,,
Various skeletal manifestations include septic arthritis, osteomyelitis, and intramedullary abscess. Skeletal involvement is more common presentation in India (16%–30%) compared to northern Australia (3%).,,
Encephalomyelitis mainly involving the brainstem is a rare manifestation seen in 4% of cases and it is geographically limited to Australia. Few cases of central nervous system (CNS) involvement are reported from Indian studies from Karnataka and Tamil Nadu.,, Other rare manifestations include mycotic aneurysm, mediastinal mass, pericardial effusion, and adrenal mass.
| Organ Transplant and Melioidosis|| |
Only a few cases of melioidosis following organ transplantation has been reported and most of them are from India.,,, The first case of melioidosis following renal transplantation was reported from south India, the patient presented with septicemia and septic arthritis, subsequently, joint aspirate and blood culture isolated B. pseudomallei. One more case was reported from the same centre, which presented 19 months following renal transplantation as pyrexia of unknown origin (PUO) and mass-like lesion on the postero-lateral wall of the urinary bladder and was diagnosed as genitourinary melioidosis. In another case report from south India, a patient presented 5 months following renal transplantation with PUO and was subsequently diagnosed as pulmonary melioidosis with involvement of mediastinal lymph nodes. All the 3 cases received injection ceftazidime in the intensive phase and had good outcomes. In a case report from northern Australia, a postrenal transplant patient presented with pleuro-pulmonary melioidosis.
| Risk of Transmission through Transplant|| |
There are no published reports of transmission of melioidosis through an organ transplant.
| Screening Recommendation|| |
Infection with B. pseudomallei can be latent and subsequently reactivated. The issue of latency and subsequent reactivation can pose a significant problem in organ transplant recipients as it can reactivate during the period of heightened immunosuppression posttransplant, however, to date no case report of reactivation from latent focus postorgan transplant has been published.
There are no recommendations for pretransplant screening for melioidosis. Even in endemic areas, blood cultures and workup for identifying a latent focus for asymptomatic donors and recipients in pretransplant screening is not recommended.
| Diagnosis|| |
Culture remains the gold standard for diagnosing melioidosis. Appropriate samples (blood, pus, urine, sputum, tissue) from various involved sites should be sent. Blood culture should be sent in all cases, as bacteremia is present in 55%–75% of cases.,,
B. pseudomallei grows on most laboratory media but more slowly than other organisms. The microbiology laboratory must be notified when B. pseudomallei is suspected and agar plates should be inspected daily and kept for 4 days. Ashdown's agar, which contains gentamicin, is a selective media that allows for the growth of B. pseudomallei. It grows well in most commercially available automated blood culture systems. There are reports of B. pseudomallei being misidentified as Acinetobacter and Pseudomonas aeruginosa. Advanced automated systems like matrix-assisted laser desorption ionization-time of flight mass spectrometry should be preferred for the identification of B. pseudomallei.
Gram stain of clinical samples and culture isolates reveal characteristic bipolar staining with a safety pin appearance. Serological tests including indirect hemagglutination are available, but they are not reliable, especially in acute melioidosis.,, In endemic areas, significant rates of antibody positivity to B. pseudomallei were observed due to previous exposure. Active Melioidosis Detect™ Lateral Flow Assay has been validated in a South Indian study with sensitivity and specificity of 86 and 93%, respectively. Owing to its poor performance in urine, it needs further validation in larger studies, however, can be of help in resource constraint settings for rapidly diagnosing melioidosis.
| Treatment|| |
The mainstay of treatment for B. pseudomallei includes beta-lactams, carbapenems, trimethoprim-sulfamethoxazole (TMP-SMX), and doxycycline. Resistance to ceftazidime is uncommon and has not been reported with meropenem. All isolates demonstrated 100% susceptibility to both ceftazidime and meropenem in an Indian study.
B. pseudomallei is inherently resistant to penicillin, first and second-generation cephalosporins, tobramycin, macrolides, and polymyxins. The treatment is divided into initial intensive therapy, followed by an eradication phase to prevent relapse. The duration of each phase is decided by the clinical syndrome.
| Intensive Therapy|| |
For patients with melioidosis who do not require intensive care unit care and do not have CNS infection, injection ceftazidime (50 mg/kg up to 2 g IV 6th hourly) is the drug of choice. In a study from Thailand, combination of ceftazidime or meropenem with TMP-SMX in the intensive phase has not been shown to provide mortality benefit or reduce rates of recurrence as compared to ceftazidime or meropenem alone.
Cefoperazone-sulbactam can be used as an alternative to ceftazidime. Higher overall treatment failure has been documented with amoxicillin-clavulanate and should be avoided in the intensive phase.
The critically ill patient should receive meropenem (1 g IV every 8 hourly) or imipenem (25 mg/kg up to 1 g IV every 6 h). Studies have demonstrated lesser treatment failure and lower mortality when carbapenem was used for critically ill patients with melioidosis., For CNS melioidosis, meropenem (2 g IV every 8 hourly) is the drug of choice.
Recombinant granulocyte colony-stimulating factor (G-CSF) has been studied in patients with melioidosis and septic shock., An Australian retrospective study with historical controls showed better survival with G-CSF use in patients with shock. A trial in Thailand also showed lower mortality in the G-CSF arm, however, it did not achieve statistical significance. G-CSF usage is at best an expert opinion at the moment.
| Eradication Phase|| |
Eradication therapy is needed to prevent relapse. It was observed that a shorter duration of oral antibiotics after the intensive phase is associated with higher rates of relapse. TMP-SMX is the preferred agent of choice for the eradication phase. The dosing of TM-SMX is described in [Box 1].
Doxycycline is an alternate inpatient who cannot tolerate TMP-SMX. Higher treatment failure and relapses have been observed with doxycycline when used as monotherapy in the eradication phase., Agents such as amoxicillin-clavulanate and fluoroquinolones are less effective in preventing relapse, compared to TMP-SMX.
MERTH trial conducted in Thailand demonstrated that monotherapy with TMP-SMX is not inferior to a combination of TMP-SMX and doxycycline. The duration of treatment of melioidosis in various organ involvement is described in [Box 2].,
| Prevention|| |
Renal transplant recipients, in the endemic areas, should avoid exposure to soil and water during rainy season and should stay indoors during natural calamities such as tsunami, dust storms, and floods.
| Prophylaxis|| |
TMP-SMX given as part of routine prophylaxis in early posttransplant period will provide protection from melioidosis. There is no recommendation to extend the TMP-SMX prophylaxis beyond the usual 6 months posttransplant for melioidosis.
| Preemptive Treatment|| |
In transplant recipients presenting with PUO after travel to endemic regions or living in endemic areas, melioidosis needs to be included in the differential diagnosis and preemptive treatment with appropriate agent active against B. pseudomallei should be initiated after necessary clinical samples are taken for Gram-stain and cultures.
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| Leptospirosis|| |
| Introduction|| |
Leptospirosis is a zoonotic disease caused by the genus Leptospira, a pathogenic spirochete. It is one of the most common zoonoses affecting rodents, cats, dogs, livestock and wild mammals. Leptospira can survive in untreated water for months or years but don't survive in saltwater or desiccation.
| Epidemiology|| |
Although leptospirosis has a worldwide distribution, it is endemic in tropical areas with heavy precipitation and high levels of subsurface water. It is endemic in South East Asia, Africa, China, Central, and South America. It occurs throughout the year, and peak incidence occurs after monsoons and heavy rainfall. In India, it is endemic in the states of Andaman and Nicobar, Gujarat, Karnataka, Kerala, Maharashtra, Odisha, and Tamil Nadu.
| Mode of Transmission|| |
There is a significant association between occupation (farmers, veterinarians, sewage workers, and animal handlers) and environmental exposure. Humans acquire infection by penetration of the bacteria through abraded skin or mucous membrane on direct contact with an animal or indirect contact with urine or blood of an infected animal.
| Clinical Features|| |
After an incubation period of 2–26 days, it can present as an anicteric febrile illness in 90% and in 10% with jaundice and other severe manifestations., So far, 5 cases of leptospirosis have been reported posttransplant, 4 cases postrenal and one postliver transplant from Brazil, Iran, the United States, and China.,,, All cases presented with Weil's disease of which one died. It is also presumed that the anicteric presentation is underdiagnosed in the transplant population living in the endemic zones. There is a possibility of transfusion-transmitted leptospirosis from donors with asymptomatic parasitemia.
| Diagnosis|| |
Leptospirosis should be considered as one of the differential diagnoses of a community-acquired febrile illness with myalgia, conjunctival suffusion, jaundice, hemorrhage, and acute renal failure, particularly in the presence of an epidemiological risk factor., Though Leptospira can be visualized in dark field microscopy and isolated from blood and urine, microscopic agglutination test (MAT), with rise in four-fold titer in a paired sample, is the gold standard. MAT is less sensitive compared to IgM ELISA which is widely used and is considered a screening test.
| Donor Screening|| |
To date, donor screening is not recommended.
| Donor Acceptance Criteria|| |
After complete recovery from the acute infection, a donor deferral period of 3 months is advised.
| Screening of Recipients from an Endemic Region|| |
Routine screening of the recipient is not recommended, however, in highly endemic regions, IgM ELISA should be done.
| Management|| |
Management of leptospirosis in posttransplant patients is the same as that recommended for the immunocompetent population. Penicillin has been the standard treatment for a long time; ceftriaxone is an alternative for severe disease. Doxycycline, azithromycin, amoxicillin, or ampicillin can be used to treat milder cases.,
| Recipients who Travel to an Endemic Region|| |
Avoid close contact with livestock and domestic animals. In the case of high-risk scenarios, chemoprophylaxis with doxycycline 200 mg once a week may be used during exposure.
| References|| |
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| Typhoid enteric fever|| |
| Introduction|| |
Enteric Fever is a severe systemic illness caused by Salmonella typhi and Paratyphi A, B, and C. The term “enteric fever” is a collective term that refers to both typhoid and paratyphoid fever, and “typhoid” and “enteric fever” are often used interchangeably. Enteric fever is associated with significant morbidity and mortality in South East Asian countries impacting not just the endemic population but international travellers also.
| Microbiology|| |
The organism classically responsible for the enteric fever syndrome is Salmonella enterica serotype Typhi. Other S. enterica serotypes that can cause a similar clinical syndrome include but are not limited to Salmonella choleraesuis, S. paratyphi A, B, and C. After ingestion, they survive exposure to gastric acid and reach the small bowel where they penetrate the epithelium, enter the lymphoid tissue, and disseminate through the lymphatic or hematogenous route. S. typhi has no known animal reservoir.
| Epidemiology|| |
More than 80% of the annual global cases occurred in South and South-East Asia and in Sub-Saharan Africa. Enteric fever is more common in children and young adults than in older patients. A recent systematic review showed that almost 10% of acute febrile illnesses seeking hospital care in India are due to Enteric fever. The incidence among children between 2 and 4 years and young adults was high in the Indian subcontinent., Population-based studies conducted in urban slums of Pakistan and India estimated the blood culture enteric positive enteric fever incidence between 184.9 and 493.5 cases per 100,000 person-years, respectively, among 5–15-year-old children. In Southeast Asia because of economic development, improved living standards for the population and immunization, enteric fever rates have declined steadily over years in Thailand and Vietnam. In some Asian countries such as Nepal, S. Typhi has shown a decreasing trend probably due to immunization while S. paratyphi A numbers are on the increase, maintaining enteric fever as a persistent problem., After malaria, enteric fever is the second leading cause of life-threatening travel-related infection. Studies from the USA, UK, Israel, and other countries reveal that most of the travel-related enteric fever appear to originate in Asia, especially the Indian subcontinent and Indonesia in Southeast Asia.,,
| Mode of Transmission|| |
Enteric fever transmission occurs through contaminated food and water systems, leading to a high burden of disease. The risk factors for typhoid fever in endemic areas include poverty, overcrowding, contaminated water, poor sanitation, and hygiene. Poor food handling practices, intake of contaminated food from street vendors, and flooding are other associated risk factors. In South Asian and South-East Asian countries, enteric fever seems to follow seasonal trends with most cases occurring following rainfall, as flooding during rainfall leads to contamination of drinking water sources with sewage.
| Risk Factors|| |
Decreased gastric acid barrier and past Helicobacter pylori infection is associated with an increased likelihood of acquiring enteric fever. Proton pump inhibitors suppress gastric acidity and this increases the risk for any enteric infections including Salmonella, although studies have mostly addressed the association with nontyphoidal salmonellosis.
The risk factors for the development of enteric fever due to S. typhi or S. paratyphi may differ. In an Indonesian study, the transmission of paratyphoid fever was more frequently observed outside the home (e.g., through consumption of food purchased from street vendors); transmission of typhoid fever was more frequently observed within the household (e.g., through sharing utensils, presence of a patient with typhoid, lack of soap, or adequate toilet facilities). Some evidence suggests that S. paratyphi may be more likely to be transmitted by food, while S. typhi may spread more through the contaminated water supply.
| Clinical Features|| |
Enteric fever has an incubation period of 2–3 weeks after ingestion of the causative microorganism in contaminated food or water.
Diarrhea is more frequently presenting symptoms in children (78% of cases) and adults with HIV, whereas constipation is seen in 30% of cases of enteric fever more so in adults.
Intestinal perforation generally occurs more frequently among adults than children and is associated with high mortality rates. In a systematic review of studies published over 20 years, the estimated case fatality rate among over 4600 typhoid patients hospitalized with intestinal perforation was approximately 15%.
Headache is a frequently reported symptom in the majority of cases, along with other neurological manifestations including disordered sleep patterns, acute psychosis, myelitis, and meningitis have been observed but are uncommon in enteric fever. In up to 17% of cases, encephalopathy may be observed with no difference in frequency among children and adults.
The clinical course of untreated enteric fever runs over several weeks and is divided into 3 characteristic stages.
- 1st week of illness - Typical stepwise rising fever with chills, bacteremia, and relative bradycardia and is observed
- 2nd week of illness - Abdominal pain and “rose spots” (faint salmon-colored macules on the trunk and abdomen) may be seen
- 3rd week of illness - Hepatosplenomegaly, intestinal bleeding, and ileocecal perforation may occur, together with secondary bacteremia and peritonitis. Septic shock or an altered level of consciousness may develop.
| Complications|| |
Complications may develop if left untreated for 3 weeks. A systematic meta-analysis clearly showed that complications are more common when there is a delay in hospitalization following symptom onset. Encephalopathy, intestinal bleeding, and intestinal perforation in the ileum or colon are commonly reported. Gastrointestinal bleeding complicates up to 10% of hospitalized patients but is often self-limited. Myocarditis is rare and probably underdiagnosed and is likely an important cause of death in enteric fever.
| Chronic Carriage|| |
Excretion of the organism in stool or urine >12 months after acute infection is called the chronic carriage. 10% of patients will continue to shed S. typhi for up to 3 months and 1%–4% for more than a year. Chronic carriage occurs more frequently in adult women and in patients with cholelithiasis or other biliary tract abnormalities and may predispose to gall bladder cancer. Chronic carriers do not develop recurrent symptomatic disease and have high serum antibody titers against the Vi antigen, but they contribute to ongoing transmission of infection as they secrete a large number of organisms. Chronic carriage rates after S. typhi varies from 1% to 6%.
| Organ Transplant and Salmonella|| |
The majority of cases in solid organ transplant recipients are due to nontyphoidal Salmonella and very few are due to S. typhi. Özgür et al. reported a case of S. typhi in a postrenal transplant on triple immunosuppression with mycophenolate mofetil, tacrolimus, and prednisolone, presenting 4-year posttransplant as a hemolytic uremic syndrome. In a series of 3 cases of Salmonella in renal transplant recipients, the disease course was more serious than in other noncompromised patients. Renal transplant recipients had prolonged carrier states and frequent relapses or recurrences of salmonellosis.
| Diagnosis|| |
Enteric fever presents as undifferentiated febrile illness and is clinically indistinguishable from many other infectious diseases such as dengue, malaria, leptospira, and scrub typhus. A protracted febrile illness of >1 week with gastrointestinal symptoms in a person living in endemic area or a traveler returning from endemic area should raise the suspicion for enteric fever.
| Blood Cultures|| |
Blood cultures have remained the gold standard for the diagnosis of enteric fever since the early 1900s. A high volume of blood sampled (e.g., two to three 20 mL blood cultures in adults) optimizes the yield of blood cultures. The sensitivity of blood culture for isolating Salmonella varies from 50% to 70% depending on the technique used. Bone marrow cultures are invasive and painful but have sensitivities varying from 80% to 96%. Bone marrow cultures are particularly helpful in patients already exposed to antibiotics.
| Nonculture-based Tests|| |
Nonculture-based tests include serology and polymerase chain reaction (PCR) assay-based tests. Widal test is available but is of limited clinical utility in endemic areas because of high rates of false-positive and negatives., When paired acute and convalescent samples are studied, a fourfold or greater increase is considered positive. Latex tests like TUBEX and Typhi-dot performed poorly and were marred by the same problem as the WIDAL test., Due to low bacterial loads during bacteremia, PCR-based tests have low sensitivity and may not be very useful in clinical practice.
| Screening Recommendation|| |
To date, donor screening is not recommended even in endemic regions. There are no published reports of transmission of Salmonella through an organ transplant.
Donor acceptance criteria
There are no published guidelines for donor acceptance after Salmonella. A deferral may be considered till the complete resolution of symptoms and affected organ functions. Donor selection postrecovery can be decided on cases to case basis in consultation with transplant physician, infectious diseases physician and transplant surgeon.
Screening of recipients from an endemic region
There are no published guidelines for recipient screening from an endemic region. Routine screening of recipients for Salmonella before organ transplant is not recommended. Typhoid vaccines may be offered to donors and transplant recipients in consultation with transplant physicians and infectious diseases physicians.
| Drug Resistance in Salmonella|| |
Over the years, resistance to the early generation quinolone nalidixic acid served as an important marker for decreased susceptibility to fluoroquinolones, however, due to the emergence of different resistance mechanisms on a few occasions nalidixic acid may be sensitive but other fluoroquinolones may be resistant. In many parts of South Asia, >80% of S. typhi isolates are nonsusceptible to fluoroquinolones. In other parts of the world, rates of fluoroquinolones are much lower. In Africa, rates of fluoroquinolone nonsusceptibility in typhoidal Salmonella remain low but are rising. The drug of choice for enteric fever is fluoroquinolone if the isolate is fluoroquinolone susceptible.
Multidrug-resistant strains (i.e., resistant to amoxicillin, trimethoprim-sulfamethoxazole [TMP-SMX], chloramphenicol) are prevalent worldwide. The prevalence of MDR strains varies, throughout Africa, the Middle East, and Central Asia, from 10% to 80%, depending on the country.,, Genome sequencing and analysis of international isolates have identified a predominant MDR S. typhi strain, H58, that has disseminated throughout Asia and Africa, displacing more susceptible strains and driving the ongoing MDR epidemic. However, on a positive note, in the surveillance of enteric fever in Asia project study, a minority of strains from India, Nepal, and Bangladesh were MDR, while the majority of strains from Pakistan continued to show multidrug resistance.
Extensively drug resistance
The majority of the Salmonella isolates are susceptible to azithromycin and ceftriaxone. resistance to ceftriaxone is increasing, with reports of patients with extended-spectrum beta-lactamase-producing S. typhi and S. paratyphi infections., A large outbreak of typhoid fever caused by a strain resistant to chloramphenicol, ampicillin, trimethoprim-sulfamethoxazole, fluoroquinolones, and third-generation cephalosporins started in Pakistan in 2016.,
| Management|| |
Based on the resistance pattern discussed above, if the infection is acquired outside Pakistan or Iraq, Ceftriaxone or azithromycin can be considered as treatment options. If the infection is acquired in Iraq or Pakistan, then due to the emergence of extended-spectrum beta-lactamase Salmonella, Meropenem for 10–14 days and azithromycin for 7 days are the only two available options for treatment. Azithromycin achieves excellent intracellular concentrations and has established efficacy even against XDR Salmonella. In a systematic review, azithromycin was at least as effective as comparators with regards to clinical failure, time to defervescence, and relapse. In an open-label, randomized study in patients with uncomplicated typhoid fever due to nalidixic acid-resistant or multidrug-resistant isolates, azithromycin resulted in a trend toward greater clinical cure rates, faster time to defervescence and lower rates of posttreatment fecal carriage. There is some data to suggest the benefit of combination therapy of azithromycin and cephalosporin in terms of reduced fever defervescence time, however, larger studies are needed to confirm this finding.,
Role of steroids
Adjunctive corticosteroids may be considered in cases of typhoidal encephalopathy. In a randomized, double-blind study performed in among 38 adults and children with severe enteric fever (shock or obtundation), the addition of high-dose dexamethasone to chloramphenicol treatment reduced mortality compared with chloramphenicol alone (10% vs. 55%). Relapses are seen in 1%–6% of cases. Relapsed infection is treated with an additional course of antibiotics, guided by susceptibility testing.
Enteric fever can be prevented by interrupting the fecal-oral transmission of Salmonella spp. Improved food and water hygiene and sanitation infrastructure significantly reduce the transmission as evidenced by the near eradication of enteric fever from industrialized countries. Typhoid outbreaks common since 1990 have been prevented following implementation of improvement in drinking water and health education among the public.
The World Health Organization recommends the implementation of national typhoid vaccination programs and also recommended for travellers to endemic areas. Vi-TT typhoid conjugate vaccine (TCV) consists of the Vi polysaccharide antigen linked to tetanus toxoid protein. In several randomized trials from Nepal, Bangladesh, and Malawi, which studied over 100,000 children, the vaccine efficacy of Typbar-TCV against culture-confirmed typhoid fever ranged from 81% to 85% compared with control vaccines.,, Vi polysaccharide vaccine consists of the Vi polysaccharide antigen. It is administered as a single intramuscular dose. In a systematic review, efficacy at 1, 2, and 3 years was 69%, 59%, and 55%. Vi polysaccharide typhoid vaccine targets Vi antigen and most S. paratyphi lack the Vi antigen, so S. paratyphi also appears to be the increasing cause of Enteric fever in vaccinated individuals. TCV vaccines appear to be more immunogenic and better at inducing long-term memory responses compared Vi-polysaccharide vaccine. Ty21a vaccine is a live oral vaccine that consists of an attenuated S. typhi strain Ty21a. It is administered in three to four doses taken on alternate days. It is comparatively less efficacious than TCV and Vi polysaccharide vaccines.
TMP-SMX given as part of routine prophylaxis in the early posttransplant period may provide protection from enteric fever, however, there are no recommendations for routine usage of TMP-SMX or any other agent as prophylaxis even in endemic areas. At the moment, literature is insufficient to recommend chemoprophylaxis for the prevention of enteric fever in a transplant recipient.
In transplant recipients presenting with community-acquired febrile illness with headache and diarrhea/constipation, in the presence of an epidemiological risk factor after travelling to endemic regions or living in endemic areas, enteric fever needs to be included in the differential diagnosis and preemptive treatment with an appropriate agent should be initiated after necessary clinical samples are taken for testing.
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| Scrub typhus|| |
| Introduction|| |
Scrub typhus is a disease vectored by trombiculid mites of the genus leptotrombidium and caused by Orientia tsutsugamushi. In Southeast Asia, scrub typhus is a leading cause of treatable nonmalarial febrile illness.
| Microbiology|| |
O. tsutsugamushi is an intracellular Gram-negative coccobacillus that is antigenically distinct from the typhus group rickettsiae. Similar to other rickettsiae, it cannot be propagated in cell-free media.
Organisms disseminate widely after initial inoculation into the skin. There are three variants or strains of O. tsutsugamushi (Karp, Gilliam, and Kato). Infection with one strain does not preclude reinfection with a different strain.
| Epidemiology|| |
O. tsutsugamushi is primarily distributed throughout the Asia Pacific rim. It is endemic in Southeast Asia (India, Pakistan, Srilanka, Thailand, and Malaysia). Scrub typhus is also endemic in Korea, China, Taiwan, Japan, and in the tropical (northern) regions of Australia. Multiple outbreaks of scrub typhus have been reported from various parts of India.,,,
| Mode of Transmission|| |
Transmission of O. tsutsugamushi may occur in sharply delineated “mite islands.” Mites live on the vegetation, and moisture and temperature conditions are ideal for the propagation of chiggers and their small rodent hosts. The risk of disease transmission from chigger bites may be extremely high when humans enter these mite infested areas. The bite of trombiculid mites or chigger which typically feeds on wild rats can lead to an infection that can range in severity from inapparent to fatal. The disease typically occurs 7–10 days after the bite of an infected chigger.
| Risk Factors|| |
Incidence rates were highest in people aged 40–60 years of age, but young children had higher rates of infection than young adults. Agriculture laborers are at increased risk of acquiring the disease in endemic areas. Scrub vegetation surrounding the house is another risk factor for disease acquisition. Rural areas, sleeping outdoors, and recent rainfall are other risk factors for scrub typhus. Among the comorbidities, diabetes mellitus and hypertension were more commonly seen in scrub typhus patients admitted to the hospital.,
| Clinical Features|| |
The severity of infection can range from mild signs and symptoms to multiorgan failure and death. Fever, headache, myalgia, nausea, vomiting, cough, altered sensorium, and seizures are common clinical presentations. Some patients may develop a characteristically nonpruritic, macular, or maculopapular rash. Lymphadenopathy, splenomegaly, relative bradycardia may be seen in some patients. Lymphocytic predominant meningoencephalitis has been reported in cases series from Thailand.
| Eschar|| |
A painless papule often develops at the site of the infecting chigger bite. Subsequent central necrosis then occurs, which in turn leads to the formation of a characteristic eschar with a black crust. Groin, abdomen, chest, and genitalia are common sites of eschar. Eschar may be often found in atypical locations such as cheek, buttocks, earlobes, dorsum of foot, and undersurface of breast and needs a thorough physical examination to locate it.
The frequency of eschars in patients with scrub typhus is highly variable and ranges from 43% to 88% in various studies from India and Korea.,,,
| Complications|| |
Acute respiratory distress syndrome (ARDS), hepatitis, meningoencephalitis, acute kidney injury (AKI), shock needing vasoactive agents, and multiorgan dysfunction syndrome were observed in 2 large series of scrub typhus from India. AKI, ARDS, jaundice, hypotension requiring vasoactive agents were independent predictors of mortality.,
| Organ Transplant and Scrub Typhus|| |
The literature review revealed only one case of scrub typhus infection in an organ transplant recipient. It was reported in a kidney transplant recipient, presenting with fever, myalgia, headache, and vomiting. She was 4 years posttransplant on triple immunosuppression (tacrolimus, MMF, and prednisolone) without any history of rejection and had stable graft function. Initially, she responded poorly to doxycycline, however, responded well to azithromycin.
| Diagnosis|| |
In the early phase of scrub typhus, no laboratory test is diagnostically reliable. Basic laboratory tests may reveal leukopenia or leukocytosis, thrombocytopenia, raised bilirubin, transaminases, and creatinine. Weil-Felix test, based on cross-reaction between anti-rickettsial antibodies and proteus antigens (OX2 and OX19), is neither specific nor sensitive and is no longer recommended to diagnose scrub typhus.
Indirect immunofluorescence assay (IFA) has been the reference test for some time; however, this technique is expensive and often unavailable in resource-limited areas where the disease is most prevalent. In addition, the interpretation of IFA results has been shown to vary greatly between operators., Because of technical difficulties of IFA and lack of cost-effectiveness, scrub typhus IgM ELISA is now preferred. ELISA detects IgM antibodies against the 56-kDa antigen, the major immunodominant protein located on the outer membrane of the bacteria, using a recombinant antigen.
IgM antibodies may be absent in the early course of the disease. Polymerase chain reaction (PCR) can also be done in patients suspected of scrub typhus to establish the diagnosis. The sensitivity of various PCR ranges from 80% to 87% and specificity is 100% in studies from China and Korea., Eschar PCR is also sensitive and specific even in cases with prior antibiotic exposure.
| Screening Recommendation|| |
To date, donor screening is not recommended. There are no published reports of transmission of scrub typhus through an organ transplant.
Donor acceptance criteria
There are no published guidelines for donor acceptance after scrub typhus. A deferral may be considered till the complete resolution of affected organ functions. Donor selection postrecovery can be decided on cases to case basis in consultation with transplant physician, infectious diseases physician, and transplant surgeon.
Screening of recipients from an endemic region
There are no published guidelines for recipient screening from an endemic region. Routine screening of recipients for scrub typhus is not recommended.
| Management|| |
Management of organ transplant recipients with scrub typhus is similar to a nonorgan transplant patient. Doxycycline (100 mg twice daily) is the drug of choice. Azithromycin can be used as an alternative.
| Prevention|| |
No vaccine is available to prevent the transmission of scrub typhus. Transplant recipient should reduce their risk of getting scrub typhus by avoiding contact with infected chiggers. When traveling to areas where scrub typhus is common, avoid areas with lots of vegetation and brush where chiggers may be found.
| Prophylaxis|| |
At the moment, the evidence to recommend chemoprophylaxis is insufficient.
| Preemptive Treatment|| |
In transplant recipients presenting with community-acquired febrile illness with fever, cough, myalgia, headache, jaundice, ARDS, and acute renal failure, in the presence of other epidemiological risk factors after traveling to endemic regions or living in endemic areas, scrub typhus needs to be included in the differential diagnosis and preemptive treatment with an appropriate agent active against scrub typhus should be initiated after necessary clinical samples are taken for testing.
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Conflicts of interest
There are no conflicts of interest.
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