Opportunistic infections (non-cytomegalovirus) in live related renal transplant recipients.

The purpose of review was increasing number of opportunistic infections with use of newer immunosuppression and difficulty in diagnosis and management of such patients. For this review, MEDLINE database was searched from 2000 to 2006 with the keywords of opportunistic infections in renal transplantation.Opportunistic infection is a serious clinical complication in patients receiving immunosuppressive therapy after kidney transplantation. The two major factors for successful renal transplantation are better control of rejection and better prevention and treatment of infection. In renal allograft recipient, immunosuppressive drug therapy is the major cause of immunocompromised status and occurrence of infections, which arise most commonly as a result of invasion by endogenous opportunists. The opportunistic infections with varicella zoster viruses, parvovirus B-19, polyomavirus, nocardia and mucormycosis in immunosuppressed patients were present with severe complications that are reviewed in this article. As a result of use of strong immunosuppressive drugs like tacrolimus, mycophenolate mofetyl and antirejection therapy with antithymocyte globulins, these infections are now seen frequently, so they should always be included in differential diagnostic consideration. New diagnostic procedures and new treatment strategies are required to allow early detection and successful treatment of opportunistic infections in kidney transplant recipients.

INTRODUCTION

The success of solid-organ transplantation, particularly renal transplantation, has markedly increased over years. The two major factors for successful renal transplantation are better control of rejection and better prevention and treatment of infection. These two are closely related and are mirror images of one another. Infectious complications are frequent in renal transplant recipients. This review summarizes novel information gathered from kidney transplant patients suffering from opportunistic infections. The term opportunistic infections are applied to an infection occurring in an immunocompromised host with impaired defense mechanisms. In other words, it is an invasive infection by a “nonpathogen” in an immunocompromised host or an infection by “sometime” or “true” pathogen of a type or severity rarely encountered in a normal host. Such infections have been on the increase for a variety of reasons. New immunosuppressive drug like mycophenolate mofetyl (MMF), tacrolimus, and the induction of immunosuppressive regimen with polyclonal antilymphocyte preparations such as anti lymphoblast globulin or antithymocyte globulins (ATG) or therapy with monoclonal antibodies (OKT3) for the treatment of steroid resistant renal allograft rejections, can foster the genesis of new opportunistic infections.[1] Furthermore, recipients and donors are often accepted for transplantation when the human leucocyte antigens are not ideally matched.

Most of the opportunistic infections occurring in renal allograft recipients are listed in Table 1. Table 2 shows various opportunistic infections (viral, bacterial, and fungal) including clinical course, diagnostic, and therapeutic options. The overall incidence of opportunistic infections varies from center to center, up to 15% of renal transplant recipients die of these infections.

Table 1

Opportunistic organisms after renal transplantation

Opportunistic organism	Time of occurrence after transplantation
Viral
Herpes simplex virus	0-2 months
Herpes viruses 6-8	1-6 months
-Polyoma BK	2 months and later
Parvovirus B-19	1 month and later
Cytomegalovirus	1 month and later
Varicella zoster virus	1-6 months
EBV	2-6 months
Bacterial
Nocardia	1-4 months (and later)
Listeria monocytogens	1-6 months (and later)
Mycobacterium tuberculosis	1-6 months (and later)
Fungal
Aspergillus fumigatus	1-4 months
Candida	0-2 months
Mucor	1 month and later
Cryptococcus neoformans	4-6 months (and later)
Pneumocystis carinii	1-6 months (and later)
Parasitic
Toxoplasma gondii	2-5 months

Table 2

Opportunistic infections after renal transplantation

Organisms	Clinical course	Diagnosis	Prevention	Treatment
Polyoma virus BK	Graft dysfunction	Urine analysis (decoy cells), serum PCR, graft biopsy	Avoidance of new immunosuppressive drugs like MMF or tacrolimus	Reduction of immunosuppression Low-dose IV cidofovir
Parvovirus B19	Erythema, pure red cell anemia, glomerulopathie, thrombotic renal graft microangiopathies	Serologic testing for parvo virus B 19 DMA, Bone marrow puncture	Not known	Ig intravenously
Varicella zoster virus	Rash, pneumonitis, encephalitis, meningitis	Course of viral load	Varicella vaccination of CRF patients	Acyclovir, Valacyclovir, famcyclovir, Varicella zoster Ig; reduction of Immunosupression
Nocardia	Pneumonia, skin nodules, brain abscesss	Chest radiograph, microbiologic testing of skin nodule puncture, cranial MRI	Not known	Meropenem + trimethoprim-sulfamethoxazole Ceftriaxone + lmipenem+
Cryptococcus neoformans	Head ache, photophobia, meningitis	Blood culture, CSF latex agglutination test	Not known	Amphotericin B + flucytosine, Fluconazole
Aspergillus fumigatus	Pneumonia, rhinosinusitis, encephalitis, cerebral abscess	Blood culture, chest radiograph, cranial CT, alveolar lavage	Avoid dust and pollens of flowers in patient rooms	Amphotericin B (lipid-based formulation), itraconazole, voriconazole
Pneumocystis carinii	Pneumonia	BAL, transbronchial biopsy	Prophylactic agents (Trimethprom + sulfamethoxazole and pentamidine)	Trimethoprim + sulfamethoxazole, pentamidine, dapsone + trimethoprim, atovoquone
Mucor	Fever, facial swelling pneumonia, cranial nerve lesions, cerebral abscess	Chest radiograph, cranial CT, alveolar lavage, blood culture	Avoid desferrioxamine in hemodialysis patients, prevent ketoacidosis	Pyrimethamine + sulfadiazine
Toxoplasma gondii	Pneumonia, meningoencephalitis, all organs can be involved	Blood culture, chest radiograph, cranial CT, histology, antibodies, DNA testing	Avoid contact with cats	Amphotericin B, surgical debridement

FACTORS CONTRIBUTING TO NET STATE OF IMMUNOSUPPRESSION IN THE RENAL TRANSPLANT RECIPIENTS

Dose, duration, and temporal sequence in which immunosuppressive agents are administered

The presence of granulocytopenia, injury to the mucocutaneous surfaces of the body

Metabolic factors such as malnutrition, uremia, and hyperglycemia

The presence of immunomodulating viral infection due to CMV, EBV, HIV, and hepatitis viruses

Polyomavirus type BK

Polyoma virus type (BK virus) associated with graft dysfunction is a rare complication in renal transplant patients. Most people are infected with the virus in childhood. The virus persist latent in urogenital tract without any symptoms in the nonimmunosuppressed host. Interstitial nephritis due to BK virus was reported in 7 of 240 patients (2.5%) receiving renal transplant.[2] Clinical features of BK virus infected patients included ureteral obstruction, lymphocele, bacterial urinary tract infection, and slow progression of azotemia due to interstitial nephritis. Tacrolimus and MMF may increase the incidence of the BK virus nephropathy. Intranuclear viral inclusion bodies in epithelial cells along the entire nephron and the transitional cell layer are hallmarks of BK virus nephropathy. Affected tubular cells are enlarged and often necrotic.[3]

Limaye et al.,[4] detected BK virus DNA in 28 sequential serum samples from all four renal transplant patients with histopathologically documented BK virus nephropathy but in none of 16 control patients. These data indicates that molecular diagnostic testing is a useful method for identifying and following patients who are at risk and those who are already affected by this condition. Decoy cells are characteristic but not pathognomonic finding in patients with BK virus nephropathy.[5]

There is currently no specific treatment available for patients with BK virus nephropathy. Therapy includes judicious lowering of doses of immunosuppressive drugs, preferably cyclosporine based, and a high level of suspicion of rejection episodes.[6] Graft failure occurs in as many as 45% of affected patients. Low-dose cidofovir (0.25 mg/kg IV every 2 weeks for 8 weeks) has been used to treat BK nephropathy.[7] Renal toxicity may result, especially with calcineurin inhibitors, although it is unclear how much BK infection contributes to the renal dysfunction. Clinical studies are needed to further evaluate the efficacy of cidofovir in the treatment of BK nephropathy. Successful retransplantation has been achieved in patients with failed allografts, usually at least 6-12 months after cessation of immune suppression.[8] Leflunomide and derivatives and fluoroquinolone antimicrobials are under investigation for BK nephropathy.[9]

Varicella zoster virus (VZV)

Herpes zoster is a frequent and serious complication of organ transplantation. VZV causes a spectrum of disease in solid-organ transplant recipients, ranging from localized dermatomal zoster (involvement of few adjoining dermatomes) to multidermatomal or disseminated zoster with or without visceral involvement. In a cohort of 869 adult organ transplant (434 renal transplant recipients), 7.4% of the renal transplant recipients had herpes zoster with a median time of onset of 9 months.[10] In seropositive pediatric patients with disseminated zoster, 3 of 19 patients (15.8%) taking MMF had generalized vesicular lesions without dermatomal distribution, within 12 months of transplantation, an uncommon event in pre MMF period.[11] Disseminated intravascular coagulation and hepatitis occurs in up to half of these patients, with pneumonitis in 29%; overall mortality rate was 34%.[11] Infection in the allograft and of the central nervous system (CNS) as well as pancreatitis has been described.

In immunocompromised hosts with zoster, direct fluorescent antibody (DFA) or tzank smear from new vesicles will assist in the diagnosis of multidermatomal or disseminated zoster. Disseminated zoster must be treated with high dose of acyclovir or valacyclovir and reduction in Immunosupression. Therapuetic use of varicella zoster immunoglobulin (VZIG) is not recommended for established varicella infection, but it has been used in some patients with disseminated or pulmonary disease. Varicella vaccination in the pretransplant period may help to protect this vulnerable population.[1012] VZIG is recommended for immunocompromised individuals with exposure to varicella or zoster, protection is incomplete.[12]

EBV/PTLD

In immunosupressed transplant recipients, primary EBV infection (and relapses in the absence of antiviral immunity) causes a mononucleosis-type syndrome, generally presenting as a lymphocytosis with or without lymphadenopathy or pharyngitis. Remitting-relapsing EBV infection is common in transplant recipients and may reflect the interplay between evolving or inadequate antiviral immunity and immune suppression.

EBV has a central role in the pathogenesis of PTLD,[13] although not all PTLD is EBV related. The most clearly defined risk factor for PTLD is primary EBV infection, which increases the risk for PTLD by 10- to 76-fold.[14] Posttransplant non-Hodgkin's lymphoma is a common complication of organ transplantation. The majority is of B-cell origin, although T cell, NK-cell, and null cell tumors have been described. T-cell PTLD has been demonstrated in 10-15% of cases, especially in the late transplant period; within allografts, it can be confused with graft rejection or other viral infection. Lymphomas comprise up to 15% of tumors among adult transplant recipients (51% in children), with mortality of 40–60%. Many deaths are associated with allograft failure after withdrawal of immune suppression during treatment of malignancy. Compared with lymphoma in the general population, PTLD has increased extranodal involvement, poorer response to conventional therapies, and poorer outcomes.

The clinical presentations of EBV-associated PTLD include: (1) unexplained fever; (2) a mononucleosis-type syndrome; (3) gastrointestinal bleeding, (4) obstruction, and perforation; (5) back pain; (6) abdominal pain or obstruction, caused by mass lesions; (7) infiltrative disease of the allograft; (8) hepatic or pancreatic dysfunction; (9) headache or other CNS disease; and (10) nodules on a chest X-ray.

Serologic testing is not useful for the diagnosis of acute EBV infection or PTLD. EBV assays are not standardized and cannot be easily compared between centers. Clinical management depends on the stage of disease. In the polyclonal form, particularly in children, reduction of immunesuppression may cause PTLD to regress. In extra-nodal disease and/or monoclonal malignant forms, reduction in immune suppression is often inadequate, with alternate therapies required. Combinations of anti-B cell therapy (anti-CD20; Rituximab), chemotherapy (CHOP), irradiation (for CNS disease), and/or adoptive immunotherapy with stimulated T cells have been used.[15] In a recent trial, 46 patients with this disorder (of whom 18 were renal transplant recipients) were treated with rituximab; immunosuppression was also reduced. The response rate at 80 days was 44% and more than half the patients achieved complete remission. Survival at 1 year was 67%. Importantly, in about 20% of patients, transplant rejection (acute and chronic) was precipitated by the immunosuppression reduction strategy. Cessation of immunosuppression may precipitate allograft loss.

Parvovirus B 19

In transplant recipients, this infection can cause erythropoietin-resistant anemia, myocarditis, pneumonitis, or pancytopenia. Direct renal involvement has been reported in renal transplant recipients with glomerulopathy and allograft dysfunction.[16] Infections may occur in the immediate posttransplant period.[16] Clinical and virological responses to treatment with intravenous immunoglobulin are usually excellent. Parvovirus B19 infection should be actively considered in transplant patients presenting with anemia or pancytopenia and allograft dysfunction.

Nocardiosis

Nocardia is a filamentous gram negative soil organism that can cause opportunistic infection in renal transplant recipients. This infection frequently disseminates to the brain and result in abscess formation. The overall mortality associated with nocardiosis in kidney transplant recipient is 25%, but this figure increased to 44% in patients who have CNS involvement.[17] Different nocardia species have been associated with human disease. Nocardia was diagnosed in 6 of 513 (1.2%) renal transplant recipients in Kuwait;[18] comorbid conditions were diabetes mellitus in three patients, viral hepatitis in two patients, neutropenia in one patient. Five patients responded well during treatment with trimethoprim-sulfamethoxazole alone or in combination with cefuroxime.[18] Imipenem, ceftrioxone, cefotaxime, meropenem, amikacin, minocycline, ampiccillin, and amoxicillin or clavulonicacid have been shown to be efficacious alone or in combination with trimethoprim + sulfamethoxazole. Cerebral abscess, if not responsive to antimicrobial therapy, should be treated surgically.[19]

Pneumonia is a very frequent complication occurring in patients with nocardiosis. Pulmonary involvement includes alveolar or interstitial infiltrates, single or multiple nodules with or without cavitations. Skin and brain are the most frequent nonpulmonary sites involved in disseminated nocardiosis.[20] Reddy and Holley[21] reported the first case of nocardiosis in a renal transplant recipient maintained on tacrolimus, Prednisolone, and mycophenolate mofetil. They suggested that the introduction of new immunosuppressive agents may increase the incidence of nocardiosis in renal transplant recipients.

Mycobaterium tuberculosis

Among the infections, tuberculosis (TB) is an important cause of morbidity in renal transplant recipients in developing world.[22] The incidence of posttransplant tuberculosis in India has been reported to be highest in the world at 5.7- 10% in various studies.[23] Most cases of Mycobacterium tuberculosis infection in kidney transplant recipients are due to reactivation of latent TB lesions. Important risk factors for reactivation include nonwhite race, history of active TB, presence of marked abnormality on a chest radiograph, exposure to person with a confirmed case of TB, and skin test positivity. In transplant patients, the clinical presentation of TB may be atypical and extrapulmonary and miliary tuberculosis is seen more frequently than in the normal population.

Tuberculosis presents numerous diagnostic difficulties in renal transplant recipients. Because of high frequency of anergy in immunosupressed patients, the mantoux test is generally unhelpful as a diagnostic tool. The classic picture of apical involvement in the general chest X-ray is seen in only a minority of renal transplant recipients with pulmonary tuberculosis.[23] Demonstration of acid-fast bacilli (AFB) in the sputum smear requires repeated examination on several occasions and has a low yield. Identification on culture takes 4-6 weeks. For these reasons, the diagnosis is often delayed, during which time the disease continues to spread. Recently, bronchoalveolar lavage (BAL) has been shown to be useful in making an early and accurate diagnosis of TB in renal transplant recipients. AFB could be identified by BAL in 88% patients with pulmonary tuberculosis.[23] Bronchoscopy and BAL should, therefore, be performed early in patients with unexplained pulmonary infiltrate in endemic areas.

Treatment of posttransplant tuberculosis presents problems both in the choice of antitubercular agents and in the duration of therapy. Rifampicin is a well-known hepatic P-450 microsomal enzyme inducer, increasing the clearance of both prednisolone and cyclosporine A. The dose of prednisolone needs to be doubled and that of cyclosporine increased to 3- to 4-fold to maintain therapeutic blood levels. The latter increases the cost of therapy and is unacceptable to a vast majority of patients. An alternative regime that has been successfully used for these patients consists of a combination of isoniazid (INH), pyrazinamide, ofloxacin, and ethambutol.[23] The optimum duration of therapy is also a matter of debate. Riska et al.,[24] recommend treatment of these patients for 9 months. This therapy may be appropriate for patients with pulormonary tuberculosis who are on both INH and rifampicin, but most centers extend the treatment to 12 months. The duration needs to be increased to 18 months in patients who are on cyclosporine and are not receiving rifampicin. The role of INH prophylaxis after transplant is controversial. In a study of 184 Indian patients, John et al.,[25] did not find any reduction in the incidence of this disease in those who received INH prophylaxis. On the other hand, INH had to be discontinued in a significant proportion of patients because of development of hepatitis. Another important concern is the development of drug-resistant tuberculosis. The incidence of primary INH resistance is increasing steadily.[26]

The American Thoracic Society recommends prophylactic INH administration to Mantoux-positive patients.[27] This strategy, however, is unlikely to be applicable in endemic areas, both because of a high degree of Mantoux positivity in the general population[28] as well as the high frequency of false negative tests among chronic renal failure (CRF) patients. Routine INH prophylaxis is therefore not recommended in endemic areas.

Fungal infections

Fungal infections after solid-organ transplantation, despite a lower incidence than bacterial and viral infections, remain a major cause of morbidity and mortality.[29] Among fungi, the responsible pathogens include Cryptococcus neoformans, Aspergillus species, Candida species, Coccidioidomyces immitis, Histoplasma capsulatum, and agents of Mucormycosis.

Aspergillosis

Aspergillus species usually cause necrotizing, rapidly progressive bronchopneumonia with fever, dyspnoea, cough, and hemoptysis. In addition, it may cause cavitations, vascular invasion, and hemorrhagic infarcts. In a retrospective analysis, 18 of 512 renal transplant patients (3.5%) were reported to have invasive fungal infections including four cases of Aspergillus pneumonia.[30] Pulmonary aspergillosis is reported in a significant proportion of renal transplant recipients in tropical countries.[31] In addition to the risk factors already mentioned ongoing construction activities in and around the hospitals and/or residential areas are responsible for increased risk of this dreaded infection. [32] Patients present with necrotizing bronchopneumonia or, less commonly, with involvement of nasal sinuses. Diagnosis requires demonstration of organisms by culture of respiratory secretions or on histology. Diagnostic sensitivity can be increased by bronchoscopy along with BAL and transbronchial biopsy. Treatment for invasive aspergillosis is with systemic amphotericin-B (conventional or liposomal), voriconazole. Fungal balls of lung or at any site required surgical removal of fungal ball and systemic therapy with Amphotericn-B. Large areas of infarction are produced because of the angioinvasive nature of this fungus, significantly reducing the penetration of the drug. If the lesion is localized, surgical resection of the infarcted areas can help by reducing the load of organism. Mortality is around 50%, increasing to over 90% in disseminated disease.

Cryptococcal

Cryptococcosis is a common fungal infection among renal transplant recipients in tropical areas.[31] The presenting symptoms are related to CNS involvement (meningoencephalitis) and include nonspecific febrile illness along with chronic headache. Although respiratory tract is the portal of entry of the organism, the symptoms related to pulmonary involvement are usually absent.[31] Lack of exudative inflammation is a characteristic feature of CNS cryptococcosis, and signs of meningeal irritation are absent in most cases. Therefore, examination of the cerebrospinal fluid, including India ink staining and cryptococcal capsular polysaccharide antigen testing, should be included in the work-up of all transplant recipients with fever of unexplained origin, especially if headache is a prominent symptom. Cutaneous nodules are the initial presentation in 30% of cases and can be diagnosed easily by biopsy. Oral fluconazole is effective in all except the most acutely ill patients, who should receive amphotericin-B. The optimal duration of therapy is unclear, and the prognosis is excellent if treatment is started in time.[31] In immunocompromised patients at least 10 weeks of therapy with amphotericin-B (conventional ampho-B 0.7-1.0 mg/kg/day, liposomal preparation 3-5mg/kg/day) followed by oral fluconazole 200 mg/day (dose should be adjusted as per GFR) indefinitely. Voriconazole should be used in patients with creatinine clearance rate below 50 ml/m. Penetration into CSF is good. Concurrent use of sirolimus is contraindicated because of its serum levels are markedly increased in the presence of voriconazole. Oral voriconazole is indicated for initial treatment of invasive aspergillosis in renal transplant recipients.

Mucormycosis (Zygomycosis)

This infection is produced by ubiquitous saprophytic fungi belonging to the order Mucorales and genera Rhizopus, Absidia, and Mucor. Airborne spores lead to primary inoculation in humans. Encountered in 0.5-1% of all transplant recipients, the risk of this infection is increased by the presence of diabetes and metabolic acidosis.[31] Presentation can take the form of fulminant rhinocerebral disease or necrotizing pneumonia with massive hemoptysis. The infection is thought to result from the donor or inoculation at the time of surgery due to poor hygienic conditions in the operation theater or the surgical wards. Diagnosis of mucormycosis is made best by biopsy and histological examination of tissues obtained by computerized tomography-guided aspiration or fine needle aspiration cytology from the involved organ. The primary treatment in these cases is prompt surgical resection of the involved areas along with systemic Amphotericn-B (deoxy cholate or liposomal preparation). The duration of therapy continued for 10-12 weeks. Voriconazole or itraconazole are of no value. Despite all these measures, the mortality exceeds 90%. Survival is rare among patients who had pulmonary, gastrointestinal, or disseminated mucormycosis.

Candidiasis

Candidiasis is the most common systemic fungal infection encountered among renal transplant recipients. Urinary tract is the site of origin in over 80% of cases.[31] The risk is increased by prolonged indwelling catheterization, urinary obstruction, and broad-spectrum antibiotics and it is also higher in diabetics. Secondary obstruction may develop due to formation of a fungal ball or renal papillary necrosis. Candida infection can also involve the lungs, usually as a secondary invader in those with a preexisting infective or noninfective pulmonary lesion. The diagnosis is made by demonstrating the organism on BAL using a sheathed catheter. Sputum culture is not diagnostic because of the possibility of contamination with pharyngeal secretion where this organism resides normally. The drug therapy includes oral fluconazole or parenteral low-dose amphotericin-B.

Pneumocystis carinii

Before the introduction of cotrimoxazole prophylaxis about 5-10% renal transplant recipients observed to develop pneumonia due to P. carinii. The frequency is higher in those on cyclosporine[32] and the period of greatest risk is between 1 and 6 months after transplantation. Interstitial pneumonia leading to respiratory failure is a cardinal feature, and the mortality approaches 60-100% in those with this complication.

The diagnosis was made with 100% sensitivity with BAL cotrimoxazole, in a dose of one single-strength tablet daily, was effective in completely preventing this infection. Once infection has already set in, treatment requires cotrimoxazole in potentially nephrotoxic doses. All patients, therefore, must receive prophylactic therapy for at least 6 months after transplant. Longer administration may be necessary in those who have received multiple courses of antirejection therapy or have graft dysfunction.

Visceral leishmaniasis

Visceral leishmaniasis (Kala-azar) is caused by the protozoan Leishmania donovani, endemic in many parts of the tropics including eastern India, parts of Africa and southwest Asia. The clinical picture is characterized by fever, weight loss, hepatosplenomegaly, cytopenias, and hypergammaglobulinemia. About 20 cases of Kala-azar have been described in renal transplant recipients; all but one had either been living in or had traveled to endemic areas.[33] The time of onset of infection varied from 3 months to 8 years following transplantation. In contrast to the nonorgan recipients, over 50% of these patients present with superinfections with bacterial, viral, or fungal organisms. The diagnosis can be established by demonstrating the organism on bone marrow examination. Treatment is with sodium stibogluconate 20 mg/day for 20-30 days. Alternatives include amphotericin B (0.5-1 mg/kg/day for a total of 10-20 mg/kg), pentamidine or a combination of allopurinol, aminosidine, or interferon-γ with antimony. More recently, liposomal amphotericin B has been used. The mortality is around 30%, and relapse is seen in about 30% of the survivors.

Toxoplasma gondii

It is an important opportunistic pathogen in heart transplant recipient and AIDS patients, it is a rare cause of clinical disease in renal transplant recipients. Unlike cardiac muscle, renal tissue rarely harbor this organism and hence disseminated primary infection of donor origin is quite rare.[34]

Cryptosporidium

Cryptosporidium is one of the intestinal protozoa belonging to the subclass of Coccidia. It is an intracellular protozoan parasite that causes gastroenteritis in humans. Infection in immunocompromised hosts may cause severe and persistent disease.[35] There are limited data on the incidence of cryptosporidiosis in the setting of solid-organ transplantation. One series found the incidence of intestinal cryptosporidiosis in kidney transplant recipients in India to be 20%. However, only 17% of these patients were symptomatic.[36] Clinical features of cryptosporidiosis vary depending on the immune status of the individual.

Patients with CD4 lymphocyte counts of <50 cells/mm3 are more likely to have fulminant or prolonged disease and higher mortality. The diagnosis of Cryptosporidium is made by identifying oocysts in stool. Serology is generally not helpful as the seroprevalence of Cryptosporidium is approximately 25-30% in North America and higher in developing countries.[37] Sensitive assays for detection of oocysts include modified acid-fast staining and DFA tests. Direct fluorescent antibodies that identify Cryptosporidium oocysts have a published sensitivity of 100% and specificity of 100%.[38] Direct immunofluorescence using monoclonal antibodies is now the gold standard for stool examination for Cryptosporidium spp.

Nitazoxanide is a relatively new antiparasitic agent with broad activity againstprotozoa and helminths. It is believed to inhibit pyruvate: ferredoxin oxidoreductase which is an essential enzyme in anerobic metabolism. Nitazoxanide at standard doses was less effective in immunocompromised patients. Immunocompromised patients may need higher doses and longer treatment courses with nitazoxanide to achieve clinical cure.[39]

Strongyloidosis

Stongyloidosis is one of the true protozoan opportunistic infection that has major effect on transplant recipients. This organism is unique among intestinal nematodes in two ways: (1) because of its ability perpetuate itself with an autoinfection cycle, it can persist in the gastrointestinal tract of individual many years after exposure. (2) The initiation of immunosuppressive therapy can result in amplification of this infestation, with tissue invasion and dissemination.[40] The diagnosis should be suspected when a patient shows peripheral eosinophilia associated with a compatible clinical picture, and can be confirmed by demonstrating the filariform larvae in the stool, body fluids, or tissue specimens. The drug of choice for this infection is thiabendazole in a dose of 50 mg/kg/day in two divided doses for 5-7 days. The efficacy of newer drugs such as albendazole and ivermectin is as yet unproved in disseminated disease.

VACCINE USE IN RENAL TRANSPLANT RECIPIENTS

Potential transplant recipients should receive immunization against influenza, pneumococcus, hepatitis-B, and varicella if they are seronegative. After transplant, many centers wait 6 months before any immunizations because of theoretical risk of stimulating the immune system and increasing the risk of rejection. Also the vaccine may be less effective during this period. The oral polio, typhoid, varicella, yellow fever, and Bacillus Calmette-Guerin vaccines are live vaccines that are contraindicated after renal transplant due to their ability to cause disease in immunocompromised hosts [Table 3]. However, the live measles-mumps-rubella (MMR) vaccine can be given after 6 months if indicated.

Table 3

Recommended vaccinations after renal transplantation

Vaccines	Recommendation
Routine vaccines
Influenza parenteral	Yearly
Influenza intra nasal	Contraindicated
Pneumococcal	Recommended, 1 time booster after 5 years
Tetanus/diphtheria	Recommended
Measles, mumps, and rubella	Contraindicated
Varicella	Contraindicated
Vaccines for selected travelers after transplantation
Hepatitis A	Recommended
Hepatitis B	Occasionally recommended
Meningococcal	Occasionally recommended
Typhim Vi	Recommended
Salmonella typhi Type 21a	Contraindicated
Oral polio	Contraindicated in patients/family members
Inactivated polio	Recommended
Rabies	Occasionally recommended
Bacillus Calmette-Guerin	Contraindicated
Yellow fever	Contraindicated
Japanese encephalitis	Occasionally recommended

CONCLUSION

Opportunistic infections remain the most important cause of morbidity and mortality among renal transplant recipients in the tropical countries. Humidity and hot environment in tropical region, lack of proper hygiene and the endemic nature of certain infections, use of newer immunosuppression molecule (tacrolimus and MMF), and increased use of antirejection therapy (IV methylprednisolone and ATG therapy) contribute to their high incidence. Frequent among these are TB, varicella zoster, and systemic fungal infections. Because of lack of proper diagnostic facilities, some of these infections frequently go unrecognized. An aggressive diagnostic approach, including use of invasive tests, is essential to make an early diagnosis for instituting timely and appropriate therapy. The goal of a clinician is the prevention of opportunistic infection by the following means: identifying and protecting the patient from excessive environmental hazards, particularly within hospital environment; and the use of antimicrobial agents either prophylactically or preemptive in order to protect against the infection promoting effects of the necessary immunosuppressive therapy. The treatment protocols need to be modified to suit the specific needs of patients in the tropical region.