Sex: M
Vaccine: COVID19
Symptoms: Alanine aminotransferase, Biopsy, Biopsy skin, Cardiac function test, Computerised tomogram abdomen
Clinical narrative: first case of new onset PTCL after COVID-19 vaccination; This is a literature report.  The patient was an 82-year-old man, with history of paroxysmal atrial fibrillation, provoked right brachiocephalic deep vein thrombosis from intravenous line insertion, peptic ulcer disease, and intermittent mild neutropenia and leukopenia, who developed a dense pruritic indurated skin lesion on the distal left arm several weeks after administration of the second Pfizer/BioNTech (BNT162b2) COVID-19 vaccine to the left arm. Subsequently, he developed additional diffuse erythematous pruritic macular lesions that covered the trunk and extremities, sparing the face and palmoplantar regions. He also noted an enlarged lymph node in the left axilla that resolved within 3-4 months after the second COVID-19 vaccination. He was seen by a dermatology specialist and was treated with topical betamethasone dipropionate 0.05% and triamcinolone 0.1%. Topical steroids minimally relieved pruritus but did not resolve the skin lesions. He was then started on cetirizine 10mg twice daily for a few months to help with pruritis and sleep, but, again, this did not resolve the skin lesions. The initial skin biopsy specimen of the left upper extremity 3 months after the onset of skin lesions showed superficial and deep infiltrate with eosinophils. A specimen from a repeated skin biopsy 4 months after the onset of skin lesions (1 month after the initial biopsy) showed eosinophilic spongiosis with an associated mixed acute and chronic dermal inflammatory cell infiltrate that contained eosinophils. Due to a persistent pruritic rash refractory to topical steroids and oral antihistamines, the patient was referred to allergy and immunology specialist 5 months after the onset of skin lesions. He stated that he did not have previous vaccine reactions as well as any changes in medication, food, cosmetic products, or detergents before the onset of skin lesions. On a review of the systems, he stated that he had no fever, night sweats, malaise, or unintentional weight loss.  Physical Examination: Vital signs were within normal limits. An examination was notable only for a diffuse blanchable maculopapular rash on the legs, arms, abdomen, back, and chest, which spared the face and palmoplantar region. On the distal left upper arm, there were three distinct raised erythematous lesions. The oral mucosa was moist, without evidence of lip, tongue, or uvular swelling, or oral lesions. The results of cardiac, pulmonary, and abdominal examinations were normal.  Laboratory findings: Complete blood cell count with differential was notable for mildly increased absolute eosinophils of 0.43 x 10^9/L (reference range of 0 -0.4 x 10^9/L), and mildly low leukocytes, neutrophils, and lymphocytes (3.3 x 10^9/L [3.8-10.6 x 10^9/L], 2.15 x 10^9/L [2.24-7.68  x 10^9/L], and 0.69  x 10^9/L [0.8-3.65 x 10^9/L], respectively). A comprehensive metabolic panel was notable for mildly elevated total protein, of 8.0g/dL (6.3-7.7 g/dL), and slightly decreased Alanine transaminase (ALT) of 12 IU/L (17-63 IU/L).  Clinical course: Due to patient's persistent generalized pruritus, the dose of oral antihistamine was increased to fexofenadine 360 mg twice a day and montelukast 10 mg nightly was started. One month later, the patient received his third COVID-19 vaccination (Pfizer/BioNTech COVID 19 booster). A week later, he noticed new indurated lesions on the posterior distal right arm. At a follow-up visit, the patient reported mildly improved pruritus but no improvement in the existing rash. Given the lack of improvement and progression of the rash, dermatology specialist was contacted for an urgent repeated biopsy. A punch biopsy was obtained from the right flank and left arm. Both biopsy specimens revealed a clonal T-cell lymphoproliferative process that was concerning for peripheral T-cell lymphoma (PTCL). The dermis demonstrated a moderately dense superficial and deep perivascular, periadnexal, and interstitial infiltrate composed predominantly of small lymphocytes and histiocytes with scattered eosinophils. T-cell receptor clonality studies were positive in both specimens.  Treatment: The patient was referred to the PTCL clinic. He reported progressive worsening of the rash, now spreading to his face and covering >80% of total body surface area. To complete the staging evaluation, both computed tomography (CT) of the chest, abdomen, and pelvis, and a full-body combined positron emission tomography (PET)/CT were obtained. The CT of the chest, abdomen, and pelvis showed mildly enlarged mesenteric and retroperitoneal lymph nodes and small indeterminate lung nodules. The PET/CT showed subtle focal areas of uptake within the left arm. There was also an increased uptake in the region of the left palatine and tongue base, and a few mildly active bilateral cervical lymph nodes and minimally avid retroperitoneal, mesenteric, and pelvic lymph nodes. The patient was started on pralatrexate infusions followed by total body radiation. Then, he was started on bexarotene but had aspiration pneumonia. Subsequently, the patient was on duvesilib, but this was stopped due to leukopenia, lower extremity edema, and the lack of disease improvement. Pembrolizumab infusions were tried, but this was also stopped due to development of new tumors. Most recently, the patient responded extremely well to doxorubicin and will ultimately transition to every 2 weeks romidepsin.  Discussion: The persistence of the patient's disseminated rash and lack of response to H1 antagonist, leukotriene receptor antagonist, and topical steroid pointed against hypersensitivity reaction. Despite two nonspecific skin biopsy results, a repeated skin biopsy was the critical step to reach the patient's diagnosis of PTCL, not otherwise specified (NOS), based on the combination of histologic features and immunohistochemistry studies. PTCL-NOS, is a heterogenous group of T-cell neoplasm with varying histologic features that manifest as lymphadenopathy or extranodal involvement, which may include the skin and gastrointestinal tract. It is an aggressive type of non-Hodgkin lymphoma that has a suboptimal response to chemotherapy, as in this case, and overall poor prognosis. PTCL is more common in men than in women, and, in the United States, the incidence of PTCL-NOS is higher in blacks compared with other races. PTCL-NOS, is a diagnosis of exclusion, in which the presence of T-cell lymphoma is confirmed based on histologic and immunochemistry studies but does not meet other PTCL subtypes based on the World Health Organization classification. Survival of patients with PTCL is very low without initiation of treatment. Various pretreatment studies, including, but not limited to, complete blood cell count with differential; comprehensive metabolic panel; lactate dehydrogenase; bone marrow biopsy; CT of the chest, abdomen, and pelvis; and full-body PET/CT, are needed to evaluate the severity and extent of the sites of involvement. A physical examination by a PTCL specialist to assess the performance status is paramount before starting and deciding on treatment.  In this case, the patient initially presented to the authors with concerns for possible delayed cutaneous COVID-19 vaccine reaction because his rash initially presented on the arm of the injection site a few weeks after the second vaccination of the primary series. However, the appearance of the patient's rash, diffuse indurated erythematous lesions, did not fit the typical type I or type IV hypersensitivity reaction presentation because it was not urticarial, not responsive to H1 antagonist and steroids, and not vesicular in appearance. H1 antagonist and leukotriene receptor antagonist only improved the pruritus but not the rash itself. A large international registry of cutaneous manifestations after COVID-19 vaccines reported urticaria as the most common cutaneous reaction for Pfizer vaccine, followed by local injection site reaction and morbilliform rash. For Moderna (Moderna Global Headquarter); (messenger RNA-1273) COVID-19 vaccine, delayed large local reaction was the most common cutaneous reaction, followed by local injection site reaction, urticaria, morbilliform rash, anderythromelalgia. This case also highlights the importance of repeated biopsy if the diagnosis is unclear and the patient's clinical presentation progresses. Because pathology results can be affected by the biopsy technique, the location and quality of the specimen must be considered. Also, it is important to consider the timing of a repeated biopsy because the histopathology may become clearer as the clinical presentation worsens. The exact etiology of the development of PTCL in this case in unknown. This patient stated that he did not have any previous diagnosed lymphoproliferative disorders but did have a history of leukopenia. There have been reports of recurrence of primary cutaneous CD30+ lymphoproliferative disorders after COVID-19 vaccines: viral vector COVID-19 vaccine (Vaxzevria,/AstraZeneca) and Pfizer COVID-19 vaccine. To the authors' knowledge, this was the first case of new onset PTCL after COVID-19 vaccination.  Final Diagnosis: PTCL  Conclusion: With new COVID-19 vaccine boosters on the horizon as the pandemic evolves to an endemic, allergist and immunologists will likely continue to see patients who are concerned about vaccine reactions manifesting with cutaneous symptoms. When the patient's presentation does not fit the typical pattern, such as persistent progressive rash in an adult unresponsive to traditional allergy medications, maintaining a high index of suspicion for an alternative diagnosis is critical. For this patient, prompt referral to dermatology specialist for a repeated skin biopsy despite two nonspecific biopsy results ultimately led to the specific diagnosis as well as initiation of life-saving therapy for an aggressive neoplastic process. This case illustrates the importance of maintaining a broad differential diagnosis for persistent rash and the necessity of a multidisciplinary approach for treating these complex patients.  No follow-up attempts are possible.; Sender's Comments: As there is limited information in the case provided, the causal association between the event peripheral T-cell lymphoma unspecified and the suspect drug BNT162B2 OMI XBB.1.5 cannot be excluded. The case will be reassessed once new information is available. The impact of this report on the benefit/risk profile of the Pfizer product is evaluated as part of Pfizer procedures for safety evaluation, including the review and analysis of aggregate data for adverse events. Any safety concern identified as part of this review, as well as any appropriate action in response, will be promptly notified to Regulatory Authorities, Ethics Committees, and Investigators, as appropriate.,Linked Report(s) : US-PFIZER INC-PV202400002494 Same article/patient/drug; different dose;