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Infectious Diseases in Clinical Practice:
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Clinical Pathological Conference

Ghanem, Khalil G. M.D.

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Department of Medicine

Johns Hopkins University

School of Medicine

This feature discloses the opinion of the discussant and the opinion of the audience by vote from the options that are listed in the differential diagnosis from the discussant. Comments are welcome (reprinted from The Johns Hokins University ID Website, http://www.hopkins-id.edu, with permission).

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A Heart Transplant Recipient with Fevers and a Pericardial Effusion

History of present illness

A 48-year-old man with a history of orthotopic heart transplant (OHT) in April 2000 and chronic renal insufficiency (baseline creatinine of 1.5 mg/dL) was admitted in August 2000 to Johns Hopkins with complaints of fevers, chills, shortness of breath, and cough. He was noted to have a small left-sided pleural effusion on chest radiograph and an increase in his serum creatinine to 2.5 mg/dL.

He was empirically started on broad-spectrum antibiotics in addition to trimethoprim-sulfamethoxazole and ganciclovir. He underwent bronchoscopy with bronchoalveolar lavage specimen; cultures and stains were negative for bacteria and fungi, but positive for cytomegalovirus (CMV) early antigen. A viral culture of the bronchoalveolar lavage specimen was positive for CMV within 24 hours. Peripheral blood CMV antigenemia was positive in 300/150,000 cells.

In view of the positive CMV studies and the lack of other pathogens, all antimicrobials were discontinued and the patient was started on induction ganciclovir, dosed appropriately for his creatinine clearance. Over the next several days, his symptoms improved and he was discharged home. Medications on discharge included ganciclovir, his immunosuppressive agents, and dapsone (which was substituted for trimethoprim-sulfamethoxazole because of worsening renal insufficiency).

In early September, while still on induction therapy for his CMV, he began to notice low-grade fevers to 38.2°C. He denied shortness of breath, cough, nausea, vomiting, diarrhea, dysuria, hematuria, headaches, visual or skin changes. The fevers persisted and the patient was admitted for further evaluation.

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Past medical history

1. OHT in April 2000, caused by idiopathic dilated cardiomyopathy. The donor was CMV seropositive (the recipient negative).

2. Non-insulin-dependent diabetes mellitus.

3. Chronic renal insufficiency with a baseline creatinine of 1.5 mg/dL.

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Medications

Prednisone, FK506, ganciclovir (2.5 mg/kg every 24 hours based on a creatinine clearance of 44 mL/min); dapsone, erythropoietin, and glyburide.

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Social history

The patient does not smoke, drink alcohol, or use illicit drugs. He lives in Baltimore City, does not have any pets, and has not traveled out of the Baltimore area in recent months.

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Physical examination

Temperature, 38.5°C; pulse, 122 beats per minute; respiratory rate, 16/min; blood pressure, 132/86; oxygen saturation on room air, 97%.

Funduscopic examination was significant for mild non-proliferative diabetic retinopathy; oropharynx was clear. Neck was soft and supple without jugular venous distention. No cervical adenopathy was noted. The thyroid gland was unremarkable. A chest examination revealed clear lungs. Cardiovascular examination was significant for tachycardia; no rubs, murmurs, or gallops were noted. Abdominal examination was benign without organomegaly. Extremities revealed trace pedal edema. Skin examination was normal. Neurologic examination was intact except for mild changes consistent with diabetic neuropathy.

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Laboratory and radiologic data

TABLE

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Differential diagnosis

1. CMV pericarditis

2. Coxsackievirus

3. Epstein-Barr virus (EBV)

4. Herpes simplex viruses (HSV)

5. Adenovirus

6. Influenza virus (A or B)

7. Streptococcus spp.

8. Staphylococcus aureus

9. Mycoplasma

10. Mycobacterium tuberculosis or non-tuberculous mycobacteria

11. Candida spp.

12. Aspergillus

13. Nocardia spp.

14. Toxoplasmosis

15. Rejection

16. Posttransplantation lymphoproliferative disorder

17. Drug-induced syndrome

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Discussion

The patient is a 48-year-old man 5 months after OHT and recently treated for disseminated CMV infection who presents with improvement of many of his original symptoms but recurrence of fever and a pericardial effusion on echocardiogram, suggesting pericardial or myopericardial inflammation.

During the first 6 months after transplantation, because of high levels of immunosuppression, transplant patients are at increased risk for many opportunistic infections. Common viral infections include herpes simplex viruses, CMV, EBV, varicella-zoster, influenza, respiratory syncytial virus, and adenoviruses.

Bacterial infections include common pathogens of postoperative infections, foreign-body-related infections, pneumonia (both community-acquired and nosocomial), and urinary tract infections. Also on the differential are nocardia, Listeria monocytogenes, and mycobacteria. Fungal infections include Pneumocystis carinii and Candida spp. Cryptococcosis typically presents later in the posttransplant course, but should be included as a cause of enigmatic fever and nonspecific symptoms. Parasitic infections encountered in the United States include toxoplasmosis and strongyloidiasis. Many of the previously noted organisms can cause myopericardial inflammation and, with the paucity of laboratory information presented, it would be difficult to narrow it down to one organism.

In the setting of recent CMV infection, certainly recurrent disease is possible in the setting of continued immune suppression, ineffective drug levels, or the emergence of resistant CMV organisms. Clinically, the patient’s symptoms had improved and his CMV antigenemia, which had been positive a month earlier, was undetectable in peripheral blood, making the diagnosis of CMV less likely. Infection with CMV has increasingly been recognized as immunosuppressing in and of itself. Infection with a second opportunistic pathogen following CMV disease is a classic clinical scenario in transplant patients.

Herpes simplex viruses are also susceptible to ganciclovir and hence unlikely pathogens in this setting. Although influenza may be isolated sporadically throughout the year, the September onset of disease in this patient makes it unlikely as the cause of his symptoms. Both Coxsackie viruses and EBV are diagnostic possibilities. EBV is universally associated with posttransplant lymphoproliferative disease, which may present with fevers and few localizing findings. Bacterial and mycobacterial causes of myopericarditis are possible, as are fungal causes, namely, in the setting of significant immune suppression.

Toxoplasmosis is a major consideration in the setting of transplantation, especially if the donor was seropositive and the recipient was seronegative. Moreover, the patient would be at increased risk of toxoplasmosis in the setting of discontinuing the trimethoprimsulfamethoxazole prophylaxis because of his renal insufficiency. Dapsone, the substituted drug for P. carinii pneumonia prophylaxis, is not effective for toxoplasmosis prophylaxis, unless combined with pyrimethamine.

Noninfectious possibilities include adverse drug reactions, and rejection of the transplanted organ.

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Discussant’s vote

Nocardiosis

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Audience’s vote

Nocardiosis

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Clinical course

The patient was admitted to the hospital. Creatine phosphokinase levels and MB fractions were mildly elevated and an electrocardiogram was unchanged from previous studies. Human immunodeficiency virus and EBV serologies were negative.

The patient underwent his routine cardiac biopsy as specified by the transplant protocol. The pathology was negative for viral inclusions, but showed evidence of mild cellular rejection and multiple cysts and tachyzoites in the myocardium, consistent with a diagnosis of toxoplasmosis (Figs. 1 and 2).

Figure 1
Figure 1
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Figure 2
Figure 2
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A chart review revealed that the patient had a negative toxoplasma serology pre-transplant whereas the donor was seropositive. He was treated with a combination of pyrimethamine and sulfadiazine and was discharged home after the rapid resolution of his symptoms. The plan is to keep the patient on a maintenance dose of anti-toxoplasma therapy until pharmacologic immunosuppression is reduced.

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Comment

Toxoplasma gondii is a ubiquitous intracellular parasite, which remains dormant in the muscles after primary infection. Seroprevalence in the United States is usually reported at 10%–30% in adults. Primary infection is generally asymptomatic in immune competent hosts or it may present as a mononucleosis-like syndrome. In the AIDS population, manifestations are most often associated with reactivation of dormant disease. In transplant patients, toxoplasmosis can occur as a result of disease reactivation (recipients that are antibody positive pre-transplant), or as a “primary” infection from a positive donor to a negative recipient. The former is quite rare, whereas the latter is not [1,2]. Primary infections can manifest as encephalitis, pneumonitis, or myocarditis and can be life-threatening.

In a study by Luft et al. [2], of 31 seronegative OHT patients, four received hearts from a seropositive donor. Three of these four patients developed primary toxoplasmosis. These results were concordant with those of several other studies, showing that more than 50% of toxoplasma mismatched transplant recipients will develop clinical disease [3].

Subsequent studies have shown that prophylaxis with the standard dose of trimethoprim-sulfamethoxazole, which is used for P. carinii prophylaxis, was effective in preventing primary toxoplasmosis in seronegative recipients of positive donors.

Some investigators have reported an increased incidence of acute toxoplasmosis in transplant patients receiving certain immunosuppressive combinations versus a lower incidence in similar patients receiving different drug combinations [4]. Subsequent studies have not confirmed this finding.

Of note, toxoplasma infection may lead to rejection in heart transplant recipients. However, the interstitial mononuclear cell infiltrate that occurs after the release of the parasite from the myocardial cells is similar to that of acute rejection. Therefore, it is difficult to determine which process predominates. The presence of eosinophils on heart biopsy specimens tends to favor toxoplasmosis over acute rejection [5].

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References

1. Fishman JA, et al. Infection in organ transplant recipients. N Engl J Med 1998; 338:1741–51.

2. Luft BJ, et al. Primary and reactivated toxoplasma infection in patients with cardiac transplants. Ann Intern Med 1983; 99:27–31.

3. Orr KE, et al. Outcome of Toxoplasma gondii mismatches in heart transplant recipients over a period of 8 years. J Infect 1994; 29:249–53.

4. Hakim M, et al. Toxoplasmosis in cardiac transplantation. Br Med J 1986; 292:1108.

5. Israelski DM, et al. Toxoplasmosis in the non-AIDS immunocompromised host. Curr Clin Topics Infect Dis 1993; 6:322–56.

© 2001 Lippincott Williams & Wilkins, Inc.