Article ID: 2024-0012-CR
Coinfection of cytomegalovirus (CMV) and Mycobacterium tuberculosis presenting with acquired perforating dermatosis is a rare occurrence and remains poorly described in the literature. A man in his 40s, a farmer and chronic smoker, who was partially treated for tuberculosis, presented with a history of fever, weight loss, cough, generalized lymphadenopathy, severe pruritus, and skin lesions. Imaging findings suggested tuberculosis, which was confirmed by sputum examination. Histopathological examinations confirmed CMV lymphadenitis associated with acquired perforating dermatosis. Treatment included antitubercular therapy and a multidrug regimen for severe pruritus, leading to symptomatic improvement. Despite initial progress, the patient was lost to follow-up and later succumbed at home, emphasizing the importance of timely intervention for coinfected tuberculosis and cytomegalovirus diseases. This case highlights the rarity of cytomegalovirus and tuberculosis coinfection, the diagnostic complexities, the challenges associated with the treatment of intractable pruritus, and the necessity of ensuring proper follow-up.
Cytomegalovirus (CMV) and Mycobacterium tuberculosis (TB) coinfection is relatively uncommon but can lead to immunologic alterations, resulting in increased severity of either infection.1 CMV lymphadenitis typically occurs in immunocompromised individuals, often following lymphoma treatment. It presents with lymphadenopathy in the neck region accompanied by mild systemic symptoms.2,3,4,5 However, partially treated TB can lead to an immunocompromised state, potentially resulting in CMV dissemination if not promptly managed.
Acquired perforating dermatosis, characterized by severe itching, is usually associated with various systemic illnesses, including infections (reported in 14% of cases). Interestingly, this condition has not been previously reported in the context of CMV or TB infections.6 Managing chronic itching in this condition is challenging unless the primary disease is effectively controlled. Nevertheless, intractable pruritus can be addressed through a multi-drug approach.
This case report sheds light on a unique clinical scenario: a patient with partially treated TB, who presented with CMV lymphadenitis and severe pruritus, ultimately succumbed during follow-up. Informed written consent was obtained from the patient for the publication of this report.
A man in his 40s, a resident of Northern India, farmer by occupation, right-handed, and a chronic smoker with a 30-pack-year history, without any comorbidities or family history of skin diseases or malignancy, and with no history of recent hospital admission or blood transfusion, presented to a tertiary care hospital with complaints of a 1-month fever that occurred about 5–6 months prior. The fever was undocumented, intermittent with an evening rise in temperature, without any chills or rigors, and was relieved with antipyretics. The patient experienced significant weight loss (undocumented) and decreased appetite. He had a cough with expectorations without hemoptysis or diurnal variation during the same period. Based on a chest X-ray at a nearby hospital, he was started on antitubercular therapy (ATT), which he continued for 3 months but stopped because of symptomatic improvement. The patient reported similar symptoms for the past 2.5 months along with nodular swelling on the right side of the neck, which also appeared in the axilla and inguinal region. The swelling was associated with pain, without any change in the surface of the skin or draining sinus. For the past 2 months, he had experienced continuous severe pruritus affecting sleep, appetite, and day-to-day activities. Erythematous papulonodular skin lesions had appeared over the trunk and limbs during the past month. The patient denied a history of shortness of breath, chest pain, hematemesis, blood transfusion, jaundice, or vomiting.
On general examination, the patient had pallor and generalized matted tender lymphadenopathy over the right cervical (size 4 × 2 cm2, nontender, firm), axillary (bilateral 4 × 2 cm2, nontender, firm), and inguinal (bilateral, size 4 × 3 cm2, nontender, firm) regions. He also had multiple well-demarcated hyperpigmented, hyperkeratotic, papules with the majority showing central umbilication and central dark brown crusting (size 0.2 × 0.2 cm2 to 1 × 1 cm2) present on the trunk and extremities, predominantly over the extensor aspect (Fig. 1A–C). On systemic examination, the patient had splenomegaly (Hackett grade III, non-tender with a smooth border) and hepatomegaly (4 cm below the right costal margin, with a smooth surface and firm border). Other systemic examinations were within normal limits.
Skin and radiographic images of the patient. (A–C) Multiple well demarcated hyperpigmented hyperkeratotic papules with majority showing central umbilication and central dark brown crusting (0.2 × 0.2 to 1 × 1 cm) present on trunk and extremities, predominantly extensor aspect. (D) High-resolution computed tomography image of thorax: bilateral fibrobronchiectatic changes in lungs with peripheral based consolidation in left upper lobe segment; centriacinar and paraseptal emphysematous changes in bilateral lobes with multiple bullae in both lungs. (E) Computed tomography of the abdomen showed hepatomegaly and splenomegaly.
Routine investigations revealed severe anemia consistent with anemia of chronic disease (Table 1). Notably, the liver function test demonstrated albumin–globulin reversal, prompting further evaluation. Serum electrophoresis revealed a polyclonal pattern with elevated gamma globulin levels without any M-band. Given the clinical picture of fever, cough, generalized lymphadenopathy, both TB and malignancy were suspected. Serology tests for hepatitis B surface antigen, anti-human immunodeficiency virus I and II antibodies, and anti-hepatitis C virus antibodies were negative by enzyme-linked immunosorbent assay. In addition, polymerase chain reaction (PCR) testing for human immunodeficiency virus (HIV) RNA was negative. Being in a resource-limited setting, serum CMV antibody titers and PCR testing were not available. A contrast-enhanced computed tomography scan of the thorax and abdomen revealed features suggestive of tuberculosis (cavitary changes, fibrobronchiectatic changes, centrilobular nodules, tree-in-bud appearance, hepatosplenomegaly) (Fig. 1D,E). Sputum examination confirmed the presence of acid-fast bacilli. The patient’s primary complaint of generalized severe pruritus prompted further evaluation for paraneoplastic syndrome considering the background of generalized lymphadenopathy and hepatosplenomegaly. Bone marrow aspiration and biopsy revealed a cellular marrow with 8% plasma cells whereas the biopsy indicated a cellular reactive marrow with mild prominence of plasma cells. Skin biopsy findings were consistent with acquired perforating dermatosis. In view of intractable pruritus, systemic symptoms, and the age of the patient, a lymph node biopsy was performed, considering the possibility of hematological malignancy. The lymph node biopsy demonstrated CMV inclusions and negative acid-fast bacilli staining along with nucleic acid amplification testing for TB (Fig. 2A–D).
| Investigation | SI unit | Reference range | Day 1 | Day 6 | Day 15 |
|---|---|---|---|---|---|
| Hb | g/dL | 13–17 | 6.4 | 9.4 | 8.5 |
| MCV | fL | 78–98 | 92 | 88.7 | 82.1 |
| TLC (×1000) | ×103 cells/mm3 | 4–11 | 4.60 | 4.55 | 7.26 |
| DLC (N/L/M) | % | 40–70/20–40/2–8 | 55/30/6.7 | 64/19/8.4 | 65/18/5.8 |
| Platelets | ×103 cells/mm3 | 150–400 | 134 | 144 | 154 |
| Total bilirubin | mg/dL | 0.3–1.2 | 1.68 | 1.61 | 0.69 |
| Direct bilirubin | mg/dL | 0–0.2 | 0.54 | 0.58 | 0.24 |
| SGPT | U/L | 0–50 | 28 | 24 | 22 |
| SGOT | U/L | 0–50 | 25 | 25 | 27 |
| ALP | U/L | 30–120 | 122 | 83 | 74 |
| GGT | U/L | 0–55 | 38 | 28 | 20 |
| Total protein | g/dL | 6.6–8.3 | 8.2 | 7.9 | 7 |
| Albumin | g/dL | 3.5–5.2 | 1.8 | 2.1 | 1.9 |
| Globulin | g/dL | 2.5–3.2 | 6.4 | 5.8 | 5.1 |
| Urea | mg/dL | 17–43 | 35 | 37 | |
| Creatinine | mg/dL | 0.72–1.18 | 0.61 | 0.75 | |
| PT/INR | 11.4/0.89 | 14.6/1.36 | 12.1/1.12 | ||
| aPTT | s | 22–35 | 22.2 | ||
| Reticulocyte count | % | 0.8 − 1.8 | 6.29 | ||
| Procalcitonin | ng/mL | <0.5 | 0.10 | ||
| LDH | IU/L | 0–248 | 355 | ||
| ESR | mm/h | 0–20 | 100 | ||
| CRP | mg/L | 0–1 | 41.8 | ||
| Folate | ng/mL | >5 | 21.6 | ||
| Vitamin B12 | pmol/L | 156–672 | >2000 | ||
| Vitamin D | ng/mL | 20–100 | 21.6 | ||
| HbA1c | % | 4.5–5.5 | 5.1% |
Hb: hemoglobin; MCV: mean corpuscular volume; TLC: total leukocyte count; DLC: differential leukocyte count; ALP: alkaline phosphatase; GGT: gamma-glutamyl transferase; LDH: lactate dehydrogenase; PT: prothrombin time; INR: international normalized ratio; aPTT: activated partial thromboplastin time; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; HbA1c: glycated hemoglobin.
Histopathology images of lymph node biopsy. (A) H&E scanner view of lymph node. (B, C) Higher magnification views (400×) showing chronic inflammatory cells with few foreign body giant cells. (D) Chronic inflammatory infiltrates comprising histiocytes and plasma cells with a foreign body-type giant cell. A large cell is noted with prominent intranuclear viral inclusion (arrow). Inset (top) shows higher magnification (1000×) of viral inclusion; inset (bottom) shows nuclear staining of anti-CMV antibody by immunohistochemistry.
Given the patient’s constellation of symptoms—fever, chronic cough, hepatosplenomegaly, and generalized lymphadenopathy in a tuberculosis endemic country—the differential diagnosis of disseminated TB was considered first, followed by lymphoma and infectious mononucleosis-like illness. Plasma cell dyscrasia and amyloidosis were also considered as differentials because of the elevated globulin and very low albumin levels, but these were ruled out by the polyclonal pattern in serum protein electrophoresis and unremarkable bone marrow examination, with a normal skeletal survey. Sputum examination confirmed tuberculosis. However, persistent, treatment-resistant intractable pruritus was a very rare presentation in this patient, leading to the consideration of a paraneoplastic etiology, for which a lymph node biopsy was also performed. The lymph node biopsy suggested CMV lymphadenitis, confirmed by immunohistochemistry with anti-CMV antibody as above. Notably, fundoscopic examination did not reveal features of CMV retinitis. After thorough evaluation, we were able to rule out hematologic malignancies, metastatic diseases, amyloidosis, and infections including HIV, Epstein–Barr virus (EBV), and syphilis. Histoplasmosis and cryptococcosis were also kept in differentials, but the histopathology confirmed the patient’s diagnosis as coinfection of TB and CMV as the underlying cause of severe pruritus.
The patient’s severe anemia was corrected with packed red blood cells. After confirming the diagnosis of pulmonary TB, he was started on ATT. He was initiated with antihistamines for pruritus, but there was no response. The dermatology team recommended coconut oil application over the body as an emollient and topical steroid ointment over the lesions, but there was no improvement. After a thorough literature review, he was started on gabapentin 300 mg once daily, increased to twice daily, and nortriptyline 10 mg, mirtazapine, along with naltrexone 25 mg once daily, which was later increased to 50 mg once daily, following which the patient had symptomatic improvement.7,8
After adding mirtazapine and increasing the dose of naltrexone, there was significant easing of pruritus. Liver function remained normal after ATT, and the patient was discharged at the request of family members. He was advised to follow up with bone marrow biopsy and lymph node histopathology reports. When the lymph node biopsy report confirmed CMV infection, a telephone enquiry 2 weeks later revealed that the patient had died at home 1week after discharge because of acute onset diarrhea and melena. Although the cause of death remained obscure, the most probable cause was disseminated CMV infection with severe gastrointestinal involvement.
A middle-aged man with partially treated TB presented with generalized lymphadenopathy and intractable pruritus. He was diagnosed with CMV lymphadenitis with acquired perforating dermatosis and subsequently died at home without proper treatment follow-up. Coinfection of TB and CMV can be fatal when not treated promptly. Although CMV–TB coinfection has been described, its presentation with severe pruritus has not been previously reported. The immunocompromised state caused by TB likely triggered the reactivation of CMV infection in this case.9
CMV lymphadenitis is rare. It is typically observed in immunocompromised cases, mostly following lymphoma treatments. It manifests as neck lymphadenopathy mimicking lymphoma.2,3,4,5 CMV lymph nodes are tender on palpation, whereas tubercular lymph nodes tend to be painless and matted, often associated with systemic and respiratory symptoms.10,11 Histologically, CMV lymph nodes exhibit follicular hyperplasia, monocytoid cell proliferation, and viral inclusions, as confirmed by immunohistochemistry in our case. In contrast, tubercular lymph nodes demonstrate granulomatous inflammation, and acid-fast staining is usually positive, although it was negative in our case.2,12
The interplay between CMV and TB alters the immunologic environment, creating a conducive environment for the pathogenesis of both diseases. CMV can persist in the body for life and may reactivate because of immunosuppression or inflammation. This reactivation leads to the proliferation of CMV-specific CD8+ and CD4+ T cells, as well as NK cells. The resulting effects, such as reduced interferon-γ secretion, KLRC2 gene deletion, and pulmonary fibrosis, can contribute to the progression of tuberculosis.13 TB manipulates cellular machinery to alter cytokine production and its protein (ESAT6), downregulating the presentation of mycobacterial peptides via the major histocompatibility complex I, causing immune dysfunction. CMV-derived viral interleukin-10 may interfere with protection against TB, whereas CMV-induced immune activation and enhanced type-I interferons can increase the risk and severity of TB disease.1 This highlights how TB can cause CMV infection, which increased the severity of the TB in our case, as demonstrated by diffuse lung cavities resulting in bullae formation. Nagahashi et al.14 reported a case of massive lower gastrointestinal bleeding in an HIV-positive patient with gastrointestinal coinfection of CMV and TB, wherein coinfection likely resulted in the increased severity of bleeding.
Acquired perforating dermatosis, an uncommon skin disorder, remains poorly understood. It typically develops in patients with underlying systemic illnesses (93%). These diseases include diabetes mellitus (49%), chronic kidney disease (28%), malignancies (15%), infectious diseases (14%), hypothyroidism (5%), rheumatological diseases (5%), and neurological diseases (4%).6 Reported infectious diseases include HIV, hepatitis C, and hepatitis B virus infections, chronic bacterial infections described in orthopedic prostheses, and hepatic abscess. Although acquired perforating dermatosis primarily affects the trunk and limbs, when presenting with hyperkeratotic papules and nodules with mild to severe pruritus, its presentation varies, often showing the Koebner phenomenon.15,16 We found a case report of cutaneous CMV infection mimicking acquired perforating dermatosis, which was diagnosed on biopsy by the demonstration of viral inclusions.17 However, the association of CMV lymphadenitis or pulmonary TB with acquired perforating dermatosis has not been previously described.
Pruritus, a distressing symptom, results from pruritogenic activation of sensory fibers. Histaminergic and non-histaminergic pathways trigger itch via selective unmyelinated C fiber neurons, transmitting signals to the spinal cord and brain through the spinothalamic tract. Patients with chronic itch exhibit peripheral and central hypersensitization, involving neurotransmitters such as glycine, GABA, and dynorphin in the spinal cord.18,19 Managing pruritus begins with antihistamines and emollients to sooth and moisturize dry skin. If these measures prove ineffective, neuroleptics like GABA analogs (pregabalin, gabapentin), antidepressants, short courses of oral corticosteroids, UV-B phototherapy, thalidomide, and opioid antagonists such as naltrexone are considered as steps on a therapeutic ladder.7,18 In our patient, naltrexone led to symptomatic improvement and is usually efficacious in dermatologic causes of pruritus.20 Coinfection of TB and CMV in apparently immunocompetent patients, presenting with severe pruritus, is a rare occurrence and presents unique diagnostic challenges. The clinical presentation of such coinfections can be atypical, as demonstrated in our case, leading to delayed diagnosis and treatment. The delay in starting treatment for CMV may have led to the fatal outcome in our case. Here, TB likely caused an immunocompromised state, which triggered CMV reactivation. This case highlights the importance of considering coinfections when clinical presentations are atypical or when treatment is inadequate. Treating the underlying TB and CMV infections remained a priority, but addressing the intractable pruritus was equally important to improve the patient’s quality of life. Dermatological complications should be considered in complex infectious disease cases, and a multidisciplinary approach may be necessary for comprehensive management.
According to the available literature, coinfections with CMV can include HIV, EBV, COVID-19, HCV, varicella, and cryptosporidiosis including TB (Table 2). However, any chronic infections can lead to immunosuppression and may be a trigger for CMV. As an underlying disease of the present patient, we ruled out hematologic malignancies, metastatic diseases, amyloidosis, sarcoidosis, rheumatologic diseases such as rheumatoid arthritis, Sjogren’s syndrome, systemic lupus erythematosus, and infections such as HIV, EBV, syphilis, histoplasmosis, and cryptococcosis from clinical settings and/or data. However, we could not rule out occult malignancies and some rare primary immunodeficiency states. Zhao et al.21 reported a CMV occurrence rate of 29% in HIV patients, suggesting major immunological failure may reactivate existing CMV in the human body. Therefore, the avoidance of immunosuppression by treating primary disease may play a major role in the prevention of CMV coinfection.
| Coinfection | Authors | Type of study | Remarks | Reference |
|---|---|---|---|---|
| HIV | Zhao et al. | Retrospective study | CMV infection rate in HIV-infected individuals was 29.05% in this study. Low CD4 count and high HIV-1 viral loads were risk factors for CMV–HIV coinfection. | 21 |
| EBV | AlAmeen et al. | Case series | EBV–CMV coinfections are uncommon in immunocompetent patients. It can sometimes result in diagnostic dilemmas and treatment should be considered to prevent complications. | 22 |
| COVID-19 | Siddiqui et al. | Case series | Described three cases presenting with severe infections. Concluded that CMV may cause severe underlying COVID-19 infection. | 23 |
| HCV | Poorna et al. | Cross-sectional study | A statistically significant association was identified between CMV and HCV. Diabetes, liver inflammation, and tuberculosis were identified as associated risk factors. | 24 |
| Varicella zoster | Bari et al. | Case report | Varicella zoster–CMV coinfection occurred in a kidney transplant patient, where early diagnosis and early start of antimicrobials are essential for preventing dissemination. | 25 |
| Varicella zoster | Isakadze et al. | Case report | Varicella zoster–CMV coinfection in an HIV-AIDS patient. Patient suffered central hypoventilation syndrome. | 26 |
| Cryptosporidiosis | Conner et al. | Case report | A case of CMV–cryptosporidiosis in HIV-AIDS patients presenting with chronic diarrhea. Study emphasized the importance of in-depth evaluation in immunocompromised patients with symptoms out of proportion to disease. | 27 |
| Tuberculosis | This case report | Case report | Intractable pruritus can be a rare presentation of TB–CMV coinfection. | - |
HIV: human immunodeficiency virus; EBV: Epstein–Barr virus; COVID-19: coronavirus disease 2019; HCV: hepatitis C virus; CMV: cytomegalovirus; AIDS: acquired immunodeficiency syndrome.
Intractable pruritus can be a rare presentation of TB–CMV coinfections. Partially treated TB can create an immunocompromised state, leading to coinfection with CMV lymphadenitis. Antidepressants and mu-opioid receptor antagonists may control chronic pruritus (itching for more than 6 weeks). However, a lack of treatment for CMV in TB coinfection can be fatal.
The authors have declared that no conflict of interest exists.
