- Email: [email protected]
Post-transplantation Infections in Bolivia
Post-transplantation Infections in Bolivia S. Arze*, L. Arze, and C. Abecia Centro Médico Quirurgico Boliviano Belga, Cochabamba, Bolivia
ABSTRACT Over 26 years, we found 46 infectious episodes in 350 kidney transplant recipients. Fifteen were urinary tract infections, recurrent in 4 patients. There were 8 cytomegalovirus infections, three of them fatal when intravenous (IV) ganciclovir was not available. Seven patients had a reactivation of tuberculosis (TB) in the pleura, cervical spine, lumbar spine, knee, ankle, skin and peritoneum, respectively, and were all resolved satisfactorily with conventional anti-TB therapy. Three patients transplanted before routine prophylaxis with the use of acyclovir developed an extensive herpes zoster infection in the 1st 6 months after transplantation, which was resolved with the use of oral acyclovir, and 1 had a disseminated herpes simplex infection resolved with the use of IV acyclovir. Three patients transplanted before routine prophylaxis with trimethoprim sulfa developed Pneumocystis carinii pneumonia in the 1st 6 months after transplantation, which was fatal in one of them. In 2 patients, we found a Nocardia infection, confined to the lung, which was cured in one of the cases and systemic and fatal in the other. Two patients transplanted before routine prophylaxis with the use of nystatin developed esophageal candidiasis in the 1st 6 months after transplantation. One patient developed infective endocarditis in a stenotic bicuspid aortic valve and died 10 years later after another incident of infective endocarditis at the prosthetic aortic valve. Two patients developed an extensive condyloma at the penis, perianal region, and perineum owing to human papillomavirus, requiring extensive surgical resection and podophyllin applications. Another patient developed fatal post-transplantation lymphoproliferative disease due to Epstein-Barr virus infection 15 years after transplantation. One patient developed a severe and fatal mucocutaneous leishmaniasis with no response to conventional antimonial therapy. It is interesting to note that despite Chagas disease being endemic in Bolivia, we had no patients with reactivation or transmission through the graft even though many of the patients and donors were serologically positive for Chagas disease.
I
NFECTIONS are an important cause of morbidity and mortality in renal transplant recipients [1e3]. Successful management is complicated by factors related to immune function in the host and the epidemiology of infection [1e3]. Transplant recipients are susceptible to a broad spectrum of infectious pathogens, manifest diminished signs and symptoms of invasive infection, and may develop systemic signs, such as fever, in response to noninfectious processes, such as graft rejection or drug toxicity, with multiple processes often present [1e3]. Immunocompromised patients tolerate invasive established infection poorly with high morbidity and mortality, lending urgency to the need for an early specific diagnosis to guide antimicrobial therapy [4]. Given 0041-1345/16 http://dx.doi.org/10.1016/j.transproceed.2016.02.049
646
the T-lymphocyte dysfunction inherent to transplantation immunosuppression, viral infections in particular are increased [1e3]. Early infections that are typical of the 1st month stem from catheters, surgical wound, the lungs, the urinary tract, or sepsis without a determined origin. Infections of the surgical wound show few signs of local inflammation. Early infections are caused by gram-positive bacteria
*Address correspondence to Silvestre Arze, MD, Nefrodial, Buenos Aires 227, Cochabamba, Bolivia. E-mail: rsarze@ nefrodial.com.bo ª 2016 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 48, 646e653 (2016)
POST-TRANSPLANTATION INFECTIONS
647
(Staphylococcus and Enterococcus) and gram-negative bacteria (Enterobacter, Pseudomonas, Acinetobacter), followed by fungi (Candida, Mucor, Aspergillus) [3]. Infections that occur starting in the 1st month and in the 1st 6 months are generally produced by opportunistic microorganisms during the period of maximum immunosuppression. After the 1st 6 months, when immunosuppression has been reduced to the minimum, the infections are those usually observed in the general population. The purpose of the present paper is to describe and comment on the infections found in our patients that have undergone renal transplantation.
METHODS As of 1987, when we performed our first renal transplantation, we designed a pilot study protocol to document the infections observed in our patients. The accumulated data over 26 years in 350 performed transplantations were assessed retrospectively and are the basis for this publication.
RESULTS
Over 26 years, we found 46 infectious episodes in 350 kidney transplant recipients. Table 1 presents the demographic features in our renal transplant population. Table 2 presents the most relevant clinical features in our 350 renal transplant recipients. And Table 3 presents the incidence of posttransplantation infections by site. Fifteen were urinary tract infections. Two occurred in the early postoperative period and were related to the urinary catheter. Four young female patients with chronic constipation and frequent genital infections had recurrent urinary tract infections that were eventually resolved. Table 1. Demographic Features in 350 Renal Transplantations Performed Characteristic
n
%
No of transplants Age: 8e68 y, mean 43 y <30 y 30e60 y >60 y Sex Male Female Donor source Living family related Living affectively related Deceased brain death Primary disease Glomerular Hypertensive Unknown Tubulointerstitial Lupus nephritis Diabetic Polycystic
350
100
80 241 28
23 69 8
180 170
51 49
289 56 5
83 16 1
126 70 62 42 28 14 8
36 20 18 12 8 4 2
Table 2. Clinical Featuresd350 Renal Transplantations Pre-transplantation CMV status IgGþ/IgM IgG/IgM Pre-transplantation EBV status IgGþ/IgM IgG/IgM Early postoperative complications Delayed graft function Urinary leak Lymphocele Acute rejection Urinary tract infection Others Long-term complications Acute rejection Chronic rejection Infections
344 6* 340 10† 14 14 12 6 2 4
4 4 3 2‡ 1 1
10 20 44
3§ 6k 13
Abbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr virus. *One patient received intravenous ganciclovir for 2 weeks and the other 5 oral valgancyclovir for 1 year. † All received oral acyclovir 400 mg twice a day for 1 year. ‡ 1 patient died after OKT3 therapy, 2 patients lost the graft, and 3 responded well to plasma exchange and intravenous immunoglobulin. § All were related to nonadherence to inmunosupressive medications (prednisone, azathioprine and cyclosporine) and partially responded to intravenous methylprednisolone. k All delayed progression after switch to mycophenolate and tacrolimus.
There were 8 cytomegalovirus (CMV) infections, all presenting with a prolonged mononucleosis-like syndrome, 1 associated with allograft dysfunction, 1 with a severe inflammatory bowel disease, and 1 with severe CNS compromise. Three were fatal when intravenous (IV) Table 3. Incidence of Post-transplantation Infections by Site Site
Systemic Nocardiosis Leishmaniosis CMV Urinary tract Pulmonary Nocardiosis Pneumocystis Pleural TB Mucocutaneous Skin TB Mucocutaneous leishmaniosis Herpes zoster Disseminated herpes simplex Digestive Esophageal candidiasis CMV-colitis CNS-CMV encephalitis Lymph nodes EBV-PTLD Osteoarticular TB Peritoneal TB Genital wartseHPV
n
1 1 4 15 1 3 1 1 1 3 1 2 1 1 1 4 1 2
Abbreviations: TB, tuberculosis; CNS, central nervous system; PTLD, posttransplantation lymphoproliferative disease; HPV, human papillomavirus; other abbreviations as in Table 2.
648
ganciclovir was not available, and the one with severe CNS compromise was fatal despite treatment with oral valganciclovir. The other 4 responded well to IV ganciclovir. Seven patients had a reactivation of tuberculosis (TB; Fig 1), each of them at a different location: pleura (Fig 1A), cervical spine (Fig 1B), lumbar spine (Fig 1C), knee (Fig 1D), ankle (Fig 1E), skin (Fig 1F), and peritoneum (Fig 1G). All of them were satisfactorily resolved with the use of conventional anti-TB therapy. The patient with pleural TB presented with fever and a pleural effusion 3 weeks after transplantation. The patient with ankle TB presented 4 months after transplantation, with pain and swelling in the left ankle on standing and walking and impaired wound healing after joint aspiration. The other 5 patients presented with local symptoms and signs in the cervical spine, lumbar spine, and knee, fever and ascites in the patient with peritoneal TB, and extensive maculopapular lesions in the patient with skin TB many years after transplantation.
Fig 1. Tuberculosis. (A) Pleura, (B) cervical spine, (C) lumbar spine, (D) knee, (E) ankle, (F) skin, (G) peritoneum.
ARZE, ARZE, AND ABECIA
Three patients transplanted before routine prophylaxis with the use of acyclovir developed, in the 1st 6 months after transplantation, an extensive herpes zoster infection between 1 and 6 months after transplantation, which was resolved with the use of oral acyclovir. One patient had a disseminated herpes simplex infection 12 years after transplantation, which was resolved with the use of IV acyclovir. Three patients transplanted before routine prophylaxis with TMP-SMZ developed a Pneumocystis carinii pneumonia in the 1st 6 months after transplantation, which was fatal in the one who presented with acute respiratory failure 2 months after transplantation (Fig 2A and B). In 2 patients, we found a Nocardia infection confined to the lung and cured in one of the patients 2 years after transplantation (Fig 3A), and systemic and fatal, related to the wound, in the other (Fig 3B) 2 months after transplantation despite prophylaxis with TMP-SMZ.
POST-TRANSPLANTATION INFECTIONS
649
Fig 2. Pneumocystis carinii pneumonia. (A) Mild x-ray findings and moderate hypoxemia. (B) Bilateral reticular opacities and severe hypoxemia.
Two patients transplanted before routine prophylaxis with the use of nystatin developed esophageal candidiasis in the 1st 6 months after transplantation. One patient developed infective endocarditis in a stenotic bicuspid aortic valve (Fig 4A) and died 10 years later after another incident infective endocarditis at the prosthetic aortic valve (Fig 4B). Two male patients developed an extensive condyloma at the penis, perianal region, and perineum owing to human papillomavirus (HPV), requiring extensive surgical resection and podophyllin applications (Fig 5). Another patient developed fatal post-transplantation lymphoproliferative disease (PTLD) due to Epstein-Barr virus (EBV) infection 15 years after transplantation, despite reduction in immunosuppression and CHOP chemotherapy. One patient with chronic graft dysfunction developed a severe and fatal mucocutaneous leishmaniasis, with no response to conventional antimonial therapy, 23 years after transplantation (Fig 6).
Fig 3. Nocardiosis. (A) Pulmonary. (B) Disseminated and related to the wound.
DISCUSSION
The risk of infection in a renal transplant recipient is determined by the interaction of the epidemiologic exposure, the timing, intensity, and virulence of the organisms, and the patient’s “net state of immunosuppression,” which reflect a measure of all host factors contributing to the risk for infection [1e3]. An understanding of these factors for each patient allows the development of differential diagnoses for infectious syndromes and preventive strategies such as prophylaxis or vaccination appropriate to each individual’s risk for infection [4,5]. Bacteremia in the first postoperative days are associated with a primary focus that sometimes is not possible to identify and requires the early initiation of broad-spectrum antibiotics to cover gram-positive and gram-negative bacteria, as well as an exhaustive search of the source [6]. In our experience, we did not find any IV catheter infection or surgical wound infection and only 2 episodes of urinary infection associated with the bladder catheter.
650
ARZE, ARZE, AND ABECIA
Fig 4. Infective endocarditis. (A) In a stenotic aortic valve. (B) In the prosthetic aortic valve.
Viral infections generally appear from the 1st month of the transplant onwards [1e3]. Herpes zoster, present in 3 of our patients, and herpes simplex, observed in 1 of our patients, due to reactivation of an earlier infection, appeared as vesicular and painful lesions on the skin and oropharynx. Nonetheless, they can be the cause of severe disseminated cases and even hepatitis. They are treated with acyclovir for 7 days, with a favorable response in almost all patients, including ours. Acyclovir is presently used on a routine basis for the 1st 6 months of the transplant and during the period of maximum immunosuppression, which effectively reduces the incidence of these infections [4]. We have been following this policy for >15 years with very good results. The herpes viruses are prominent, given the importance of T-cell function in antiviral control and the disproportionate degree of T-cell inhibition by most immunosuppressive regimens [1e3]. CMV is the most common viral infection in the transplant patient [1e3]. It is primary if the recipient is seronegative and the disease is transmitted by a seropositive graft, a situation not observed in our experience [7e9]. Reactivation is most frequent when the recipient is seropositive and the latent virus is replicated because of immunosuppression, a situation observed in our 8 patients. It presents with fever
along with general discomfort, myalgia, and leukopenia, as observed in all of our patients. There can be skin rashes, alteration of liver function, and thrombocytopenia. The most serious is interstitial pneumonia without pathognomonic signs. It can be the cause of hepatitis; meningoencephalitis, as happened with 1 of our patients; multiple ulcers in the gastrointestinal tract, which usually manifest themselves by digestive hemorrhages, as observed in 1 of our female patients, or perforation of the hollow viscus, especially in the colon; pancreatitis; and retinitis. It is diagnosed by means of CMV antigen detection, which was positive in all of our patients. Detection by means of viral DNA polymerase chain reaction (PCR) has sensitivity and specificity similar to antigen detection, a technique that is so far not available in our setting. The usefulness of serologic tests is debatable, given the time required for seroconversion and that the production of IgM antibodies can be blocked by immunosuppression. However, we observed an increase of IgG levels and a positivization of IgM in all of our patients. It is treated with 2 doses of IV ganciclovir for 10e14 days, which was used with good results in 5 of our 8 patients after it became available in Bolivia [4]. Viral infections not only contribute to graft dysfunction, graft rejection, and systemic illness, but also enhance the
Fig 5. Human papillomavirus Infection. (A) Penis. (B) Anal and perineal region.
POST-TRANSPLANTATION INFECTIONS
651
Fig 6. Mucocutaneus leishmaniosis. (A) Destruction of the nasal septum. (B) Destruction of the palate.
risk for bacterial, fungal, or other opportunistic infections such as Pneumocystis carinii and virally mediated cancers, as occurred in one of our patients with PTLD resulting from an EBV infection. EBV infection occurs from the 1st month onward in up to two-thirds of seronegative recipients, and reinfection occurs in one-third of seropositive recipients [1e3]. It is the cause of various lymphoproliferative clinical pictures that range from noncomplicated mononucleosis, without tonsillitis or adenopathy, to PTLD, which can be localized or widespread affecting the lymph nodes and organs, as happened in our patient. PTLPD is usually fatal, and the risk of PTLPD increases in case of a concomitant CMV infection [10]. Prophylaxis is achieved with acyclovir administered in the 1st 6 months after transplantation with good results; it also is a policy that we have followed in the past 15 years [4]. Treatment involves reducing immunosuppression and, in serious cases, with the same drug, but with doubtful effectiveness [4]. Human papillomavirus infection causes warts in different parts of the body [11]. More than 40 different strains of HPV affect the genital area. Some types of HPV can cause cancer of the cervix [12]. Vaccines can protect against the strains of genital HPV most likely to cause genital lesions or cervical cancer [13]. Genital warts may appear as flat lesions, small cauliflower-like bumps, or tiny stem-like protrusions. In men, genital lesions may appear on the penis and scrotum or around the anus, as in our 2 patients. In women, genital warts appear most commonly in the vulva but may also occur near the anus, on the cervix, or in the vagina. HPV infection occurs when the virus enters the body through a cut, abrasion, or small tear in the outer layer of the skin. The virus is transferred primarily by skin-to-skin contact. Genital HPV infections are contracted through sexual intercourse, anal sex, and other skin-to-skin contact in the genital region [14]. Genital warts occur most often in adolescents and young adults, such as our patients. People who have weakened immune systems owing to immune systemesuppressing drugs used after organ transplants, as our patients, are at greater risk of HPV infections. HPV infection is diagnosed after visual inspection of the lesions.
Genital lesions are treated with podofilox, a topical product that destroys genital wart tissue. If the lesions are extensive, as in our 2 patients, they should be physically removed by freezing with liquid nitrogen, burning with electrocautery, surgical removal, as in our 2 patients, or laser surgery followed by podofilox applications. Tuberculosis is endemic in Bolivia. Recent and remote exposures to Mycobacterium tuberculosis can result in localized pulmonary, systemic, or metastatic infection [15]. Post-transplantation TB in any of its forms is due to an endogenous reactivation favored by immunosuppression, a situation observed in 7 of our patients. The clinical manifestations are the usual ones in this disease in different sites. The high incidence of joint TB, including the cervical spine, lumbar spine, knee, and ankle, in 4 of our patients is striking. Treatment with 4 drugs, isoniazid, rifampin, pyrazinamide, and ethambutol, at the usual dosages for the 1st 2 months, and continuing with the first 2 drugs for 4e8 additional months is recommended, associated with surgical treatment in the case of joint TB. Latent infections, such as TB, may activate many years after the initial exposure, as occurred in 6 of our patients. Such infections may be difficult to treat when established owing to interactions between the antimicrobial agents used to treat them, especially rifampin and the agents used in immunosuppressive therapy, particularly cyclosporine, thus requiring an increase of the dosage according to monthly blood levels. Pneumonia due to Pneumocystis carinii presents with fever, cough, and shortness of breath on exertion for 2e3 weeks. However, it occasionally presents with sudden-onset acute respiratory failure, as in 1 of our patients. Chest x-ray shows interstitial or bilateral alveolar infiltration. In severe cases, there is hypoxemia with disproportionate hypocapnia. The laboratory results are nonspecific. It is diagnosed by visualization of the cysts or Pneumocystis carinii trophozoites in respiratory secretions. At present, PCR is available to determine the presence of this microorganism in the fluid, but the technique is still unavailable in our setting. Induced sputum is the 1st method used owing to its high profitability and ease. If it is negative, bronchoscopy with bronchoalveolar lavage is diagnostic in almost 100% of the
652
patients. Pneumonia is prevented with the use of oral TMP/ SMZ in the 1st 6 months after transplantation and treated with the use of TMP/SMZ orally or intravenously, with good results, as happened in 2 of our patients. Nocardiosis occurs in cutaneous, pulmonary, and disseminated forms [16], producing suppurative necrosis with abscess formation at sites of infection. Pleuropulmonary nocardiosis manifests as an acute or subacute pneumonitis, usually in immunocompromised hosts, as occurred in 1 of our patients [17], and arises from inhalation exposure [18]. Disseminated nocardiosis may involve any organ and results from hematogenous dissemination, usually from a pulmonary or subcutaneous focus, as occurred in 1 of our patients. The cutaneous forms arise from local traumatic inoculation. Dissemination from these sites is more likely in immunocompromised hosts, particularly those with impaired cell-mediated immunity such as renal transplant patients under immunosuppressive therapy. Most individuals have underlying immunocompromising disease or are receiving immunosuppressive therapy. Primary cutaneous nocardiosis may present as either cellulitis or single or multiple nontender erythematous nodules at the site of traumatic inoculation, draining purulent material. Pulmonary disease is the predominant clinical finding in most patients. Clinical manifestations include inflammatory endobronchial masses or localized or diffuse pneumonia, which may be accompanied by cavitation, abscess formation, pleural effusion, or empyema. Cough with sputum production and fever are the dominant symptoms. Pulmonary and disseminated nocardiosis are clearly associated with immunocompromising conditions, with 60% of cases occurring in individuals with some compromise of host defense systems including solid-organ transplantation. Nocardiosis has a variable prognosis, depending on the site and extent of infection and underlying host factors. Cure rates with appropriate therapy are w100% in skin and soft-tissue infections. Ninety percent of pleuropulmonary infections can be cured with appropriate therapy, as occurred in 1 of our patients. The cure rate in disseminated nocardiosis falls to 63%. Specific antimicrobial therapy is the mainstay of medical care, recommended for 6 months. In patients under immunosuppressive therapy, such therapy can be continued while appropriate specific therapy for nocardiosis is administered. TMP-SMZ is the therapy of choice. Duration of treatment is prolonged to minimize the risk of relapse. Immunosuppressed patients should receive 12 months of therapy, or longer if higher immunosuppression is required, as in graft rejection. TMP-SMZ prophylaxis for 6 months in solid-organ transplant recipients may decrease the likelihood of nocardiosis. Fungal infections are frequent. Candida causes >80% of the episodes. It usually causes infection in the surgical wound or candidemia that sometimes originates at the venous catheter, particularly in the 1st month, and more frequently at the oropharynx and the esophagus, as happened in 2 of our patients in the 1st 6 months after transplantation. Oropharyngeal and esophageal candidiasis
ARZE, ARZE, AND ABECIA
is treated with fluconazole, used in our 2 patients with very good results. Fluconazole inhibits cytochrome p450 activity, increasing cyclosporine and tacrolimus levels and therefore requiring the reduction of these drugs’ dosages. Mucocutaneus leishmaniasis, present in 1 of our patients, is caused by Leishmania braziliensis, and represents a major health problem in tropical areas of South America [19,20]. In our case, the patient accompanied his wife, a nurse at a leprosarium in the middle of the jungle. The usual reservoirs are rodents and dogs. The vector is the female Phlebotomus insect and the hosts are human reticuloendothelial system cells. A small indurated papule appears after the insect bite, followed by ulceration with overprotruded borders and a central scab [21,22]. Without treatment, 15% of the cases evolve into a mucocutaneous leishmaniasis, with the destruction of the nasal cartilage and soft palate, causing extensive mutilation with involvement of the underlying tissue [23,24], as happened in our patient. It is diagnosed through an exhaustive examination of the lesions and the epidemiologic background of permanence in endemic areas, as happened in our patient. Biopsy shows intramacrophagic parasites. It is treated with parenteral meglumine antimoniate (20 mg/kg/d) for a month, adjusting the dose to renal function. Prognosis depends on the virulence of the causal agent and the patient’s immunologic state, which in our case was much compromised by cumulative immunosuppression after 23 years of the transplant and chronic graft dysfunction. Chagas disease due to Trypanosoma cruzi has been transmitted by transplantation in endemic areas such as Bolivia and more recently in the United States [25]. However, we have never seen a transplant patient with primary infection transmitted through the graft or reactivation due to immunosuppression, even though Chagas disease is endemic in Bolivia and most of our patients and donors were seropositive for Chagas at the time of transplantation. We conclude that infections after renal transplantation in Bolivia are similar to those found in other places, and many of them are preventable with antiviral, antibacterial, or antifungal prophylaxis. Reactivation of endemic diseases, such as TB, is common and related to immunosuppression. Finally, epidemiologic exposures of the patient and the “net state of immunosuppression,” can explain occasional infections such as mucocutaneus leishmaniasis. REFERENCES [1] Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med 2007;357:2601. [2] Fishman JA, Issa NC. Infection in organ transplantation: risk factors and evolving patterns of infection. Infect Dis Clin North Am 2010;24:273. [3] Green M. Introduction: Infections in solid organ transplantation. Am J Transplant 2013;13(Suppl 4):3. [4] Blumberg EA, Danziger-Isakov L, Kumar D. Foreword: guidelines 3. Am J Transplant 2013;13(Suppl 4):1. [5] Chong PP, Razonable RR. Diagnostic and management strategies for donor-derived infections. Infect Dis Clin North Am 2013;27:253.
POST-TRANSPLANTATION INFECTIONS [6] Kalil AC, Syed A, Rupp ME. Is bacteremic sepsis associated with higher mortality in transplant recipients than in nontransplant patients? A matched case-control propensity-adjusted study. Clin Infect Dis 2015;60:216. [7] Morris MI, Fischer SA, Ison MG. Infections transmitted by transplantation. Infect Dis Clin North Am 2010;24:497. [8] Fishman JA, Greenwald MA, Grossi PA. Transmission of infection with human allografts: essential considerations in donor screening. Clin Infect Dis 2012;55:720. [9] Green M, Covington S, Taranto S. Donor-derived transmission events in 2013: a report of the Organ Procurement Transplant Network Ad Hoc Disease Transmission Advisory Committee. Transplantation 2015;99:282. [10] Reshef R, Vardhanabhuti S, Luskin MR, Heitjan DF, Hadjiliadis D, Goral S. Reduction of immunosuppression as initial therapy for posttransplantation lymphoproliferative disorder. Am J Transplant 2011;11:336e47. [11] Monk BJ, Tewari KS. The spectrum and clinical sequelae of human papillomavirus infection. Gynecol Oncol 2007;107(Suppl 1): S6e13. [12] Paternoster DM, Cester M, Resente C. Human papilloma virus infection and cervical intraepithelial neoplasia in transplanted patients. Transplant Proc 2008;40:1877e80. [13] Avery RK, Michaels M. Update on immunizations in solid organ transplant recipients: what clinicians need to know. Am J Transplant 2008;8:9e14. [14] Bonnez W, Reichman R. Papillomaviruses. In: Mandell GL, Bennett JE, Dolin R, editors. Principles and practice of infectious diseases. 6th ed. Philadelphia: Churchill Livingstone; 2006. p. 1841e56.
653 [15] Aguado JM, Torre-Cisneros J, Fortún J. Tuberculosis in solid-organ transplant recipients: consensus statement of the Group for the Study of Infection in Transplant Recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology. Clin Infect Dis 2009;48:1276. [16] Wilson JW. Nocardiosis: updates and clinical overview. Mayo Clin Proc 2012;87:403e7. [17] Filice GA. Nocardiosis in persons with human immunodeficiency virus infection, transplant recipients, and large, geographically defined populations. J Lab Clin Med 2005;145:156e62. [18] Peleg AY, Husain S, Qureshi ZA. Risk factors, clinical characteristics, and outcome of Nocardia infection in organ transplant recipients: a matched case-control study. Clin Infect Dis 2007;44:1307e14. [19] Antinori S, Cascio A, Parravicini C. Leishmaniasis among organ transplant recipients. Lancet Infect Dis 2008;8:191. [20] Tomson N, Symonds RP, Moir AA, Kendal CH, Wiselka MJ. New world leishmaniasis from Spain. Postgrad Med J 2002;78:757e8. [21] Shareef MM, Trotter MI, Cullen RJ. Leishmaniasis of the nasal cavity: a case report. J Laryngol Otol 2005;119:1015e7. [22] Galioto P, Fornaro V. A case of mucocutaneous leishmaniasis. Ear Nose Throat J 2002;81:46e8. [23] Hernández CA. Natural history of cutaneous and mucocutaneous leishmaniasis. Biomedica 2006;26:10e2. [24] Weller PF, Durand ML, Pilch BZ. Case 4-2005. A 35-yearold man with nasal congestion, swelling, and pain. N Engl J Med 2005;352:609e15. [25] Centers for Disease Control and Prevention (CDC). Chagas disease after organ transplantationdLos Angeles, California, 2006. MMWR Morb Mortal Wkly Rep 2006;55:798.
ABSTRACT Over 26 years, we found 46 infectious episodes in 350 kidney transplant recipients. Fifteen were urinary tract infections, recurrent in 4 patients. There were 8 cytomegalovirus infections, three of them fatal when intravenous (IV) ganciclovir was not available. Seven patients had a reactivation of tuberculosis (TB) in the pleura, cervical spine, lumbar spine, knee, ankle, skin and peritoneum, respectively, and were all resolved satisfactorily with conventional anti-TB therapy. Three patients transplanted before routine prophylaxis with the use of acyclovir developed an extensive herpes zoster infection in the 1st 6 months after transplantation, which was resolved with the use of oral acyclovir, and 1 had a disseminated herpes simplex infection resolved with the use of IV acyclovir. Three patients transplanted before routine prophylaxis with trimethoprim sulfa developed Pneumocystis carinii pneumonia in the 1st 6 months after transplantation, which was fatal in one of them. In 2 patients, we found a Nocardia infection, confined to the lung, which was cured in one of the cases and systemic and fatal in the other. Two patients transplanted before routine prophylaxis with the use of nystatin developed esophageal candidiasis in the 1st 6 months after transplantation. One patient developed infective endocarditis in a stenotic bicuspid aortic valve and died 10 years later after another incident of infective endocarditis at the prosthetic aortic valve. Two patients developed an extensive condyloma at the penis, perianal region, and perineum owing to human papillomavirus, requiring extensive surgical resection and podophyllin applications. Another patient developed fatal post-transplantation lymphoproliferative disease due to Epstein-Barr virus infection 15 years after transplantation. One patient developed a severe and fatal mucocutaneous leishmaniasis with no response to conventional antimonial therapy. It is interesting to note that despite Chagas disease being endemic in Bolivia, we had no patients with reactivation or transmission through the graft even though many of the patients and donors were serologically positive for Chagas disease.
I
NFECTIONS are an important cause of morbidity and mortality in renal transplant recipients [1e3]. Successful management is complicated by factors related to immune function in the host and the epidemiology of infection [1e3]. Transplant recipients are susceptible to a broad spectrum of infectious pathogens, manifest diminished signs and symptoms of invasive infection, and may develop systemic signs, such as fever, in response to noninfectious processes, such as graft rejection or drug toxicity, with multiple processes often present [1e3]. Immunocompromised patients tolerate invasive established infection poorly with high morbidity and mortality, lending urgency to the need for an early specific diagnosis to guide antimicrobial therapy [4]. Given 0041-1345/16 http://dx.doi.org/10.1016/j.transproceed.2016.02.049
646
the T-lymphocyte dysfunction inherent to transplantation immunosuppression, viral infections in particular are increased [1e3]. Early infections that are typical of the 1st month stem from catheters, surgical wound, the lungs, the urinary tract, or sepsis without a determined origin. Infections of the surgical wound show few signs of local inflammation. Early infections are caused by gram-positive bacteria
*Address correspondence to Silvestre Arze, MD, Nefrodial, Buenos Aires 227, Cochabamba, Bolivia. E-mail: rsarze@ nefrodial.com.bo ª 2016 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 48, 646e653 (2016)
POST-TRANSPLANTATION INFECTIONS
647
(Staphylococcus and Enterococcus) and gram-negative bacteria (Enterobacter, Pseudomonas, Acinetobacter), followed by fungi (Candida, Mucor, Aspergillus) [3]. Infections that occur starting in the 1st month and in the 1st 6 months are generally produced by opportunistic microorganisms during the period of maximum immunosuppression. After the 1st 6 months, when immunosuppression has been reduced to the minimum, the infections are those usually observed in the general population. The purpose of the present paper is to describe and comment on the infections found in our patients that have undergone renal transplantation.
METHODS As of 1987, when we performed our first renal transplantation, we designed a pilot study protocol to document the infections observed in our patients. The accumulated data over 26 years in 350 performed transplantations were assessed retrospectively and are the basis for this publication.
RESULTS
Over 26 years, we found 46 infectious episodes in 350 kidney transplant recipients. Table 1 presents the demographic features in our renal transplant population. Table 2 presents the most relevant clinical features in our 350 renal transplant recipients. And Table 3 presents the incidence of posttransplantation infections by site. Fifteen were urinary tract infections. Two occurred in the early postoperative period and were related to the urinary catheter. Four young female patients with chronic constipation and frequent genital infections had recurrent urinary tract infections that were eventually resolved. Table 1. Demographic Features in 350 Renal Transplantations Performed Characteristic
n
%
No of transplants Age: 8e68 y, mean 43 y <30 y 30e60 y >60 y Sex Male Female Donor source Living family related Living affectively related Deceased brain death Primary disease Glomerular Hypertensive Unknown Tubulointerstitial Lupus nephritis Diabetic Polycystic
350
100
80 241 28
23 69 8
180 170
51 49
289 56 5
83 16 1
126 70 62 42 28 14 8
36 20 18 12 8 4 2
Table 2. Clinical Featuresd350 Renal Transplantations Pre-transplantation CMV status IgGþ/IgM IgG/IgM Pre-transplantation EBV status IgGþ/IgM IgG/IgM Early postoperative complications Delayed graft function Urinary leak Lymphocele Acute rejection Urinary tract infection Others Long-term complications Acute rejection Chronic rejection Infections
344 6* 340 10† 14 14 12 6 2 4
4 4 3 2‡ 1 1
10 20 44
3§ 6k 13
Abbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr virus. *One patient received intravenous ganciclovir for 2 weeks and the other 5 oral valgancyclovir for 1 year. † All received oral acyclovir 400 mg twice a day for 1 year. ‡ 1 patient died after OKT3 therapy, 2 patients lost the graft, and 3 responded well to plasma exchange and intravenous immunoglobulin. § All were related to nonadherence to inmunosupressive medications (prednisone, azathioprine and cyclosporine) and partially responded to intravenous methylprednisolone. k All delayed progression after switch to mycophenolate and tacrolimus.
There were 8 cytomegalovirus (CMV) infections, all presenting with a prolonged mononucleosis-like syndrome, 1 associated with allograft dysfunction, 1 with a severe inflammatory bowel disease, and 1 with severe CNS compromise. Three were fatal when intravenous (IV) Table 3. Incidence of Post-transplantation Infections by Site Site
Systemic Nocardiosis Leishmaniosis CMV Urinary tract Pulmonary Nocardiosis Pneumocystis Pleural TB Mucocutaneous Skin TB Mucocutaneous leishmaniosis Herpes zoster Disseminated herpes simplex Digestive Esophageal candidiasis CMV-colitis CNS-CMV encephalitis Lymph nodes EBV-PTLD Osteoarticular TB Peritoneal TB Genital wartseHPV
n
1 1 4 15 1 3 1 1 1 3 1 2 1 1 1 4 1 2
Abbreviations: TB, tuberculosis; CNS, central nervous system; PTLD, posttransplantation lymphoproliferative disease; HPV, human papillomavirus; other abbreviations as in Table 2.
648
ganciclovir was not available, and the one with severe CNS compromise was fatal despite treatment with oral valganciclovir. The other 4 responded well to IV ganciclovir. Seven patients had a reactivation of tuberculosis (TB; Fig 1), each of them at a different location: pleura (Fig 1A), cervical spine (Fig 1B), lumbar spine (Fig 1C), knee (Fig 1D), ankle (Fig 1E), skin (Fig 1F), and peritoneum (Fig 1G). All of them were satisfactorily resolved with the use of conventional anti-TB therapy. The patient with pleural TB presented with fever and a pleural effusion 3 weeks after transplantation. The patient with ankle TB presented 4 months after transplantation, with pain and swelling in the left ankle on standing and walking and impaired wound healing after joint aspiration. The other 5 patients presented with local symptoms and signs in the cervical spine, lumbar spine, and knee, fever and ascites in the patient with peritoneal TB, and extensive maculopapular lesions in the patient with skin TB many years after transplantation.
Fig 1. Tuberculosis. (A) Pleura, (B) cervical spine, (C) lumbar spine, (D) knee, (E) ankle, (F) skin, (G) peritoneum.
ARZE, ARZE, AND ABECIA
Three patients transplanted before routine prophylaxis with the use of acyclovir developed, in the 1st 6 months after transplantation, an extensive herpes zoster infection between 1 and 6 months after transplantation, which was resolved with the use of oral acyclovir. One patient had a disseminated herpes simplex infection 12 years after transplantation, which was resolved with the use of IV acyclovir. Three patients transplanted before routine prophylaxis with TMP-SMZ developed a Pneumocystis carinii pneumonia in the 1st 6 months after transplantation, which was fatal in the one who presented with acute respiratory failure 2 months after transplantation (Fig 2A and B). In 2 patients, we found a Nocardia infection confined to the lung and cured in one of the patients 2 years after transplantation (Fig 3A), and systemic and fatal, related to the wound, in the other (Fig 3B) 2 months after transplantation despite prophylaxis with TMP-SMZ.
POST-TRANSPLANTATION INFECTIONS
649
Fig 2. Pneumocystis carinii pneumonia. (A) Mild x-ray findings and moderate hypoxemia. (B) Bilateral reticular opacities and severe hypoxemia.
Two patients transplanted before routine prophylaxis with the use of nystatin developed esophageal candidiasis in the 1st 6 months after transplantation. One patient developed infective endocarditis in a stenotic bicuspid aortic valve (Fig 4A) and died 10 years later after another incident infective endocarditis at the prosthetic aortic valve (Fig 4B). Two male patients developed an extensive condyloma at the penis, perianal region, and perineum owing to human papillomavirus (HPV), requiring extensive surgical resection and podophyllin applications (Fig 5). Another patient developed fatal post-transplantation lymphoproliferative disease (PTLD) due to Epstein-Barr virus (EBV) infection 15 years after transplantation, despite reduction in immunosuppression and CHOP chemotherapy. One patient with chronic graft dysfunction developed a severe and fatal mucocutaneous leishmaniasis, with no response to conventional antimonial therapy, 23 years after transplantation (Fig 6).
Fig 3. Nocardiosis. (A) Pulmonary. (B) Disseminated and related to the wound.
DISCUSSION
The risk of infection in a renal transplant recipient is determined by the interaction of the epidemiologic exposure, the timing, intensity, and virulence of the organisms, and the patient’s “net state of immunosuppression,” which reflect a measure of all host factors contributing to the risk for infection [1e3]. An understanding of these factors for each patient allows the development of differential diagnoses for infectious syndromes and preventive strategies such as prophylaxis or vaccination appropriate to each individual’s risk for infection [4,5]. Bacteremia in the first postoperative days are associated with a primary focus that sometimes is not possible to identify and requires the early initiation of broad-spectrum antibiotics to cover gram-positive and gram-negative bacteria, as well as an exhaustive search of the source [6]. In our experience, we did not find any IV catheter infection or surgical wound infection and only 2 episodes of urinary infection associated with the bladder catheter.
650
ARZE, ARZE, AND ABECIA
Fig 4. Infective endocarditis. (A) In a stenotic aortic valve. (B) In the prosthetic aortic valve.
Viral infections generally appear from the 1st month of the transplant onwards [1e3]. Herpes zoster, present in 3 of our patients, and herpes simplex, observed in 1 of our patients, due to reactivation of an earlier infection, appeared as vesicular and painful lesions on the skin and oropharynx. Nonetheless, they can be the cause of severe disseminated cases and even hepatitis. They are treated with acyclovir for 7 days, with a favorable response in almost all patients, including ours. Acyclovir is presently used on a routine basis for the 1st 6 months of the transplant and during the period of maximum immunosuppression, which effectively reduces the incidence of these infections [4]. We have been following this policy for >15 years with very good results. The herpes viruses are prominent, given the importance of T-cell function in antiviral control and the disproportionate degree of T-cell inhibition by most immunosuppressive regimens [1e3]. CMV is the most common viral infection in the transplant patient [1e3]. It is primary if the recipient is seronegative and the disease is transmitted by a seropositive graft, a situation not observed in our experience [7e9]. Reactivation is most frequent when the recipient is seropositive and the latent virus is replicated because of immunosuppression, a situation observed in our 8 patients. It presents with fever
along with general discomfort, myalgia, and leukopenia, as observed in all of our patients. There can be skin rashes, alteration of liver function, and thrombocytopenia. The most serious is interstitial pneumonia without pathognomonic signs. It can be the cause of hepatitis; meningoencephalitis, as happened with 1 of our patients; multiple ulcers in the gastrointestinal tract, which usually manifest themselves by digestive hemorrhages, as observed in 1 of our female patients, or perforation of the hollow viscus, especially in the colon; pancreatitis; and retinitis. It is diagnosed by means of CMV antigen detection, which was positive in all of our patients. Detection by means of viral DNA polymerase chain reaction (PCR) has sensitivity and specificity similar to antigen detection, a technique that is so far not available in our setting. The usefulness of serologic tests is debatable, given the time required for seroconversion and that the production of IgM antibodies can be blocked by immunosuppression. However, we observed an increase of IgG levels and a positivization of IgM in all of our patients. It is treated with 2 doses of IV ganciclovir for 10e14 days, which was used with good results in 5 of our 8 patients after it became available in Bolivia [4]. Viral infections not only contribute to graft dysfunction, graft rejection, and systemic illness, but also enhance the
Fig 5. Human papillomavirus Infection. (A) Penis. (B) Anal and perineal region.
POST-TRANSPLANTATION INFECTIONS
651
Fig 6. Mucocutaneus leishmaniosis. (A) Destruction of the nasal septum. (B) Destruction of the palate.
risk for bacterial, fungal, or other opportunistic infections such as Pneumocystis carinii and virally mediated cancers, as occurred in one of our patients with PTLD resulting from an EBV infection. EBV infection occurs from the 1st month onward in up to two-thirds of seronegative recipients, and reinfection occurs in one-third of seropositive recipients [1e3]. It is the cause of various lymphoproliferative clinical pictures that range from noncomplicated mononucleosis, without tonsillitis or adenopathy, to PTLD, which can be localized or widespread affecting the lymph nodes and organs, as happened in our patient. PTLPD is usually fatal, and the risk of PTLPD increases in case of a concomitant CMV infection [10]. Prophylaxis is achieved with acyclovir administered in the 1st 6 months after transplantation with good results; it also is a policy that we have followed in the past 15 years [4]. Treatment involves reducing immunosuppression and, in serious cases, with the same drug, but with doubtful effectiveness [4]. Human papillomavirus infection causes warts in different parts of the body [11]. More than 40 different strains of HPV affect the genital area. Some types of HPV can cause cancer of the cervix [12]. Vaccines can protect against the strains of genital HPV most likely to cause genital lesions or cervical cancer [13]. Genital warts may appear as flat lesions, small cauliflower-like bumps, or tiny stem-like protrusions. In men, genital lesions may appear on the penis and scrotum or around the anus, as in our 2 patients. In women, genital warts appear most commonly in the vulva but may also occur near the anus, on the cervix, or in the vagina. HPV infection occurs when the virus enters the body through a cut, abrasion, or small tear in the outer layer of the skin. The virus is transferred primarily by skin-to-skin contact. Genital HPV infections are contracted through sexual intercourse, anal sex, and other skin-to-skin contact in the genital region [14]. Genital warts occur most often in adolescents and young adults, such as our patients. People who have weakened immune systems owing to immune systemesuppressing drugs used after organ transplants, as our patients, are at greater risk of HPV infections. HPV infection is diagnosed after visual inspection of the lesions.
Genital lesions are treated with podofilox, a topical product that destroys genital wart tissue. If the lesions are extensive, as in our 2 patients, they should be physically removed by freezing with liquid nitrogen, burning with electrocautery, surgical removal, as in our 2 patients, or laser surgery followed by podofilox applications. Tuberculosis is endemic in Bolivia. Recent and remote exposures to Mycobacterium tuberculosis can result in localized pulmonary, systemic, or metastatic infection [15]. Post-transplantation TB in any of its forms is due to an endogenous reactivation favored by immunosuppression, a situation observed in 7 of our patients. The clinical manifestations are the usual ones in this disease in different sites. The high incidence of joint TB, including the cervical spine, lumbar spine, knee, and ankle, in 4 of our patients is striking. Treatment with 4 drugs, isoniazid, rifampin, pyrazinamide, and ethambutol, at the usual dosages for the 1st 2 months, and continuing with the first 2 drugs for 4e8 additional months is recommended, associated with surgical treatment in the case of joint TB. Latent infections, such as TB, may activate many years after the initial exposure, as occurred in 6 of our patients. Such infections may be difficult to treat when established owing to interactions between the antimicrobial agents used to treat them, especially rifampin and the agents used in immunosuppressive therapy, particularly cyclosporine, thus requiring an increase of the dosage according to monthly blood levels. Pneumonia due to Pneumocystis carinii presents with fever, cough, and shortness of breath on exertion for 2e3 weeks. However, it occasionally presents with sudden-onset acute respiratory failure, as in 1 of our patients. Chest x-ray shows interstitial or bilateral alveolar infiltration. In severe cases, there is hypoxemia with disproportionate hypocapnia. The laboratory results are nonspecific. It is diagnosed by visualization of the cysts or Pneumocystis carinii trophozoites in respiratory secretions. At present, PCR is available to determine the presence of this microorganism in the fluid, but the technique is still unavailable in our setting. Induced sputum is the 1st method used owing to its high profitability and ease. If it is negative, bronchoscopy with bronchoalveolar lavage is diagnostic in almost 100% of the
652
patients. Pneumonia is prevented with the use of oral TMP/ SMZ in the 1st 6 months after transplantation and treated with the use of TMP/SMZ orally or intravenously, with good results, as happened in 2 of our patients. Nocardiosis occurs in cutaneous, pulmonary, and disseminated forms [16], producing suppurative necrosis with abscess formation at sites of infection. Pleuropulmonary nocardiosis manifests as an acute or subacute pneumonitis, usually in immunocompromised hosts, as occurred in 1 of our patients [17], and arises from inhalation exposure [18]. Disseminated nocardiosis may involve any organ and results from hematogenous dissemination, usually from a pulmonary or subcutaneous focus, as occurred in 1 of our patients. The cutaneous forms arise from local traumatic inoculation. Dissemination from these sites is more likely in immunocompromised hosts, particularly those with impaired cell-mediated immunity such as renal transplant patients under immunosuppressive therapy. Most individuals have underlying immunocompromising disease or are receiving immunosuppressive therapy. Primary cutaneous nocardiosis may present as either cellulitis or single or multiple nontender erythematous nodules at the site of traumatic inoculation, draining purulent material. Pulmonary disease is the predominant clinical finding in most patients. Clinical manifestations include inflammatory endobronchial masses or localized or diffuse pneumonia, which may be accompanied by cavitation, abscess formation, pleural effusion, or empyema. Cough with sputum production and fever are the dominant symptoms. Pulmonary and disseminated nocardiosis are clearly associated with immunocompromising conditions, with 60% of cases occurring in individuals with some compromise of host defense systems including solid-organ transplantation. Nocardiosis has a variable prognosis, depending on the site and extent of infection and underlying host factors. Cure rates with appropriate therapy are w100% in skin and soft-tissue infections. Ninety percent of pleuropulmonary infections can be cured with appropriate therapy, as occurred in 1 of our patients. The cure rate in disseminated nocardiosis falls to 63%. Specific antimicrobial therapy is the mainstay of medical care, recommended for 6 months. In patients under immunosuppressive therapy, such therapy can be continued while appropriate specific therapy for nocardiosis is administered. TMP-SMZ is the therapy of choice. Duration of treatment is prolonged to minimize the risk of relapse. Immunosuppressed patients should receive 12 months of therapy, or longer if higher immunosuppression is required, as in graft rejection. TMP-SMZ prophylaxis for 6 months in solid-organ transplant recipients may decrease the likelihood of nocardiosis. Fungal infections are frequent. Candida causes >80% of the episodes. It usually causes infection in the surgical wound or candidemia that sometimes originates at the venous catheter, particularly in the 1st month, and more frequently at the oropharynx and the esophagus, as happened in 2 of our patients in the 1st 6 months after transplantation. Oropharyngeal and esophageal candidiasis
ARZE, ARZE, AND ABECIA
is treated with fluconazole, used in our 2 patients with very good results. Fluconazole inhibits cytochrome p450 activity, increasing cyclosporine and tacrolimus levels and therefore requiring the reduction of these drugs’ dosages. Mucocutaneus leishmaniasis, present in 1 of our patients, is caused by Leishmania braziliensis, and represents a major health problem in tropical areas of South America [19,20]. In our case, the patient accompanied his wife, a nurse at a leprosarium in the middle of the jungle. The usual reservoirs are rodents and dogs. The vector is the female Phlebotomus insect and the hosts are human reticuloendothelial system cells. A small indurated papule appears after the insect bite, followed by ulceration with overprotruded borders and a central scab [21,22]. Without treatment, 15% of the cases evolve into a mucocutaneous leishmaniasis, with the destruction of the nasal cartilage and soft palate, causing extensive mutilation with involvement of the underlying tissue [23,24], as happened in our patient. It is diagnosed through an exhaustive examination of the lesions and the epidemiologic background of permanence in endemic areas, as happened in our patient. Biopsy shows intramacrophagic parasites. It is treated with parenteral meglumine antimoniate (20 mg/kg/d) for a month, adjusting the dose to renal function. Prognosis depends on the virulence of the causal agent and the patient’s immunologic state, which in our case was much compromised by cumulative immunosuppression after 23 years of the transplant and chronic graft dysfunction. Chagas disease due to Trypanosoma cruzi has been transmitted by transplantation in endemic areas such as Bolivia and more recently in the United States [25]. However, we have never seen a transplant patient with primary infection transmitted through the graft or reactivation due to immunosuppression, even though Chagas disease is endemic in Bolivia and most of our patients and donors were seropositive for Chagas at the time of transplantation. We conclude that infections after renal transplantation in Bolivia are similar to those found in other places, and many of them are preventable with antiviral, antibacterial, or antifungal prophylaxis. Reactivation of endemic diseases, such as TB, is common and related to immunosuppression. Finally, epidemiologic exposures of the patient and the “net state of immunosuppression,” can explain occasional infections such as mucocutaneus leishmaniasis. REFERENCES [1] Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med 2007;357:2601. [2] Fishman JA, Issa NC. Infection in organ transplantation: risk factors and evolving patterns of infection. Infect Dis Clin North Am 2010;24:273. [3] Green M. Introduction: Infections in solid organ transplantation. Am J Transplant 2013;13(Suppl 4):3. [4] Blumberg EA, Danziger-Isakov L, Kumar D. Foreword: guidelines 3. Am J Transplant 2013;13(Suppl 4):1. [5] Chong PP, Razonable RR. Diagnostic and management strategies for donor-derived infections. Infect Dis Clin North Am 2013;27:253.
POST-TRANSPLANTATION INFECTIONS [6] Kalil AC, Syed A, Rupp ME. Is bacteremic sepsis associated with higher mortality in transplant recipients than in nontransplant patients? A matched case-control propensity-adjusted study. Clin Infect Dis 2015;60:216. [7] Morris MI, Fischer SA, Ison MG. Infections transmitted by transplantation. Infect Dis Clin North Am 2010;24:497. [8] Fishman JA, Greenwald MA, Grossi PA. Transmission of infection with human allografts: essential considerations in donor screening. Clin Infect Dis 2012;55:720. [9] Green M, Covington S, Taranto S. Donor-derived transmission events in 2013: a report of the Organ Procurement Transplant Network Ad Hoc Disease Transmission Advisory Committee. Transplantation 2015;99:282. [10] Reshef R, Vardhanabhuti S, Luskin MR, Heitjan DF, Hadjiliadis D, Goral S. Reduction of immunosuppression as initial therapy for posttransplantation lymphoproliferative disorder. Am J Transplant 2011;11:336e47. [11] Monk BJ, Tewari KS. The spectrum and clinical sequelae of human papillomavirus infection. Gynecol Oncol 2007;107(Suppl 1): S6e13. [12] Paternoster DM, Cester M, Resente C. Human papilloma virus infection and cervical intraepithelial neoplasia in transplanted patients. Transplant Proc 2008;40:1877e80. [13] Avery RK, Michaels M. Update on immunizations in solid organ transplant recipients: what clinicians need to know. Am J Transplant 2008;8:9e14. [14] Bonnez W, Reichman R. Papillomaviruses. In: Mandell GL, Bennett JE, Dolin R, editors. Principles and practice of infectious diseases. 6th ed. Philadelphia: Churchill Livingstone; 2006. p. 1841e56.
653 [15] Aguado JM, Torre-Cisneros J, Fortún J. Tuberculosis in solid-organ transplant recipients: consensus statement of the Group for the Study of Infection in Transplant Recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology. Clin Infect Dis 2009;48:1276. [16] Wilson JW. Nocardiosis: updates and clinical overview. Mayo Clin Proc 2012;87:403e7. [17] Filice GA. Nocardiosis in persons with human immunodeficiency virus infection, transplant recipients, and large, geographically defined populations. J Lab Clin Med 2005;145:156e62. [18] Peleg AY, Husain S, Qureshi ZA. Risk factors, clinical characteristics, and outcome of Nocardia infection in organ transplant recipients: a matched case-control study. Clin Infect Dis 2007;44:1307e14. [19] Antinori S, Cascio A, Parravicini C. Leishmaniasis among organ transplant recipients. Lancet Infect Dis 2008;8:191. [20] Tomson N, Symonds RP, Moir AA, Kendal CH, Wiselka MJ. New world leishmaniasis from Spain. Postgrad Med J 2002;78:757e8. [21] Shareef MM, Trotter MI, Cullen RJ. Leishmaniasis of the nasal cavity: a case report. J Laryngol Otol 2005;119:1015e7. [22] Galioto P, Fornaro V. A case of mucocutaneous leishmaniasis. Ear Nose Throat J 2002;81:46e8. [23] Hernández CA. Natural history of cutaneous and mucocutaneous leishmaniasis. Biomedica 2006;26:10e2. [24] Weller PF, Durand ML, Pilch BZ. Case 4-2005. A 35-yearold man with nasal congestion, swelling, and pain. N Engl J Med 2005;352:609e15. [25] Centers for Disease Control and Prevention (CDC). Chagas disease after organ transplantationdLos Angeles, California, 2006. MMWR Morb Mortal Wkly Rep 2006;55:798.