Infections in Transplant, Asplenic & Immunosuppressed Hosts

Overview: matching the defect to the pathogen

Infection risk in an immunocompromised patient reflects what the patient is exposed to (hospital flora, latent viruses in the body or the graft, food, soil, pets, travel) and which arm of host defense is missing. Solid-organ transplant (SOT) recipients mainly lose T-cell immunity, so intracellular bacteria, herpesviruses, fungi and parasites dominate. Asplenic patients cannot clear encapsulated bacteria and blood-borne parasites. Patients on biologic agents have narrow defects that mirror the pathway the drug blocks. Because immunosuppressants blunt fever and inflammation, infections present subtly and progress fast, so the threshold for evaluation and empiric therapy is low.

The post-transplant timeline

Time since transplant is the most useful single clue. The classic pattern assumes standard prophylaxis and a stable maintenance regimen; treating rejection with pulse glucocorticoids or antithymocyte globulin resets the clock and reopens the opportunistic window.

Specific pairings. Toxoplasma is classically a problem in heart recipients, because cysts persist in the myocardium of a seropositive donor heart. Listeria causes meningitis, rhombencephalitis and bacteremia with cell-mediated defects, so empiric meningitis therapy in a transplant recipient adds ampicillin to vancomycin plus a third-generation cephalosporin (cephalosporins never cover Listeria).

Live vaccines (MMR, varicella, yellow fever, intranasal influenza) are contraindicated after transplant, so immunizations are updated during the pretransplant evaluation.

Prophylaxis after transplant

TMP-SMX. Low-dose trimethoprim-sulfamethoxazole, typically for the first 6–12 months (longer after lung transplant or intensified immunosuppression), prevents Pneumocystis, Toxoplasma and Nocardia, with incidental Listeria and urinary coverage. Sulfa-intolerant patients receive atovaquone, dapsone (after G6PD testing) or inhaled pentamidine, which prevent PJP but do not dependably cover Nocardia. Breakthrough nocardiosis can still occur on low-dose TMP-SMX.

CMV risk. After SOT the highest-risk pairing is a seropositive donor with a seronegative recipient (D+/R−): the recipient has no CMV-specific memory T cells and acquires primary infection from the graft. Seropositive recipients (R+) have intermediate risk from reactivation; D−/R− recipients have the lowest risk and should receive CMV-safe (seronegative or leukoreduced) blood. Lung and intestinal grafts and antithymocyte globulin induction add risk. In allogeneic stem-cell transplantation the seropositive recipient is the high-risk host.

Universal versus preemptive strategy. Universal prophylaxis gives valganciclovir to all at-risk recipients for about 3–6 months (longest for D+/R− recipients and after lung transplant); drawbacks are leukopenia and late-onset CMV once the drug stops. Preemptive therapy monitors CMV PCR, usually weekly, and starts treatment-dose valganciclovir when viremia crosses a threshold; it requires dependable follow-up. Letermovir, a terminase inhibitor with little marrow toxicity, is used for prophylaxis in seropositive allogeneic stem-cell recipients and high-risk (D+/R−) kidney recipients.

HSV and VZV. Ganciclovir and valganciclovir are active against HSV and VZV, so acyclovir or valacyclovir is added only for patients not receiving them (including those on letermovir).

CMV disease, BK virus and PTLD

CMV presentations. CMV syndrome is fever, malaise, leukopenia or thrombocytopenia and mild transaminitis with viremia. Tissue-invasive disease most often involves the GI tract (esophagitis, colitis with ulcers and bleeding), liver, lungs (interstitial pneumonitis) and the allograft; retinitis is uncommon outside advanced HIV. CMV also increases the risk of rejection and of bacterial and fungal superinfection.

Diagnosis and treatment. Quantitative plasma CMV PCR is the workhorse; serology is useless for active disease after transplant. Because blood PCR can be low or negative in GI disease, colitis is confirmed by biopsy showing enlarged cells with "owl's-eye" inclusions, confirmed by immunohistochemistry. IV ganciclovir is used for severe or tissue-invasive disease and oral valganciclovir for mild to moderate disease, for at least 2 weeks and until viremia clears, while lowering immunosuppression when feasible. Acyclovir is not reliable against CMV.

Resistance. A viral load that keeps rising despite adequate ganciclovir suggests a UL97 mutation, which blocks the drug's first phosphorylation. Switching to foscarnet requires hydration and close monitoring of creatinine, calcium, magnesium and potassium, since low ionized calcium causes paresthesias and seizures.

BK polyomavirus. BK reactivates in kidney recipients, mostly in the first year, causing tubulointerstitial nephritis and ureteral stenosis with a rising creatinine that mimics rejection. Plasma BK PCR screening detects it early; urine shows "decoy cells," and biopsy shows intranuclear inclusions staining for SV40. Treatment is to reduce immunosuppression, because no antiviral is reliably effective. In stem-cell recipients BK more often causes hemorrhagic cystitis.

Post-transplant lymphoproliferative disorder. Without EBV-specific T-cell control, EBV-infected B cells proliferate, producing anything from a mononucleosis-like illness to aggressive lymphoma with lymphadenopathy, GI or allograft masses, or CNS lesions. Risk is greatest in EBV-seronegative recipients (often children) of seropositive organs, in the first year, and after T-cell–depleting therapy. Diagnosis requires biopsy; management starts with reducing immunosuppression, then rituximab with or without chemotherapy.

Calcineurin inhibitor interactions

Why they matter. Tacrolimus and cyclosporine (and sirolimus and everolimus) are CYP3A4 and P-glycoprotein substrates with narrow therapeutic windows monitored by trough levels. Excess causes nephrotoxicity, hypertension, hyperkalemia, hypomagnesemia, tremor and hyperglycemia (especially tacrolimus); cyclosporine also causes gingival hyperplasia and hirsutism. Low levels cause rejection.

• Raise levels: azoles (voriconazole, posaconazole, itraconazole, fluconazole), clarithromycin and erythromycin, diltiazem and verapamil, grapefruit juice. Azithromycin barely affects CYP3A4 and is the preferred macrolide.
• Lower levels: rifampin (rifabutin less so), phenytoin, carbamazepine, phenobarbital and St John's wort.

Whenever an azole, macrolide or rifamycin is started or stopped, check the calcineurin inhibitor trough and adjust the dose. TMP-SMX adds to tacrolimus-induced hyperkalemia.

Asplenia

Mechanism. The spleen filters poorly opsonized bacteria and parasitized red cells and houses IgM memory B cells that respond to polysaccharide capsules. Asplenia follows splenectomy (trauma, ITP, hereditary spherocytosis) or functional loss, classically autosplenectomy in sickle cell disease. Howell-Jolly bodies on the smear signal absent splenic function.

Overwhelming post-splenectomy infection (OPSI). Encapsulated organisms, above all Streptococcus pneumoniae, then Haemophilus influenzae type b and Neisseria meningitidis, progress from a flu-like prodrome to septic shock, DIC and purpura within hours, with mortality up to about 50%. Risk is highest in children and in the first years after surgery but lasts for life. Other threats are Capnocytophaga canimorsus, a gram-negative rod in dog saliva that causes fulminant sepsis with purpura, DIC and gangrene after bites or licks; high-parasitemia babesiosis after Ixodes tick exposure in the Northeast and Upper Midwest (atovaquone plus azithromycin, exchange transfusion if severe); and severe falciparum malaria.

Prevention. Vaccinate at least 14 days before elective splenectomy, or at least 14 days after an emergency splenectomy: pneumococcal conjugate vaccine (PCV20 or PCV21, or PCV15 followed by PPSV23), a 2-dose MenACWY series with boosters every 5 years, a MenB series, Hib if not previously vaccinated, and yearly inactivated influenza vaccine. Patients carry standby amoxicillin-clavulanate to start at the first fever while seeking care, receive antibiotics after any dog bite, and take strict antimalarial chemoprophylaxis for travel. Children with sickle cell disease take daily penicillin from about 2 months until 5 years of age.

Biologic and drug-specific risks

Mechanistic links. TNF-α builds and maintains granulomas, so blocking it releases contained TB and dimorphic fungi; the monoclonal antibodies (infliximab, adalimumab) carry more TB risk than the soluble receptor etanercept. Rituximab-related HBV reactivation can be fulminant even after resolved infection, so screening precedes the first dose. Terminal complement forms the membrane attack complex that kills Neisseria, which is why C5 blockade raises meningococcal risk roughly 1,000–2,000-fold and fever in these patients needs urgent evaluation even after vaccination.