Deadly Duo: A Common Infection and an Undiagnosed Medical Condition

A 7-year-old boy with a past medical history of bicuspid aortic valve, multiple congenital physical anomalies and Hirschsprung disease status postcolostomy presents with 2 weeks of a diffuse petechial rash and daily fevers greater than 100.4 °F. His rash was initially erythematous and papular in nature but then became smooth and macular. The rash started on his forearms then quickly spread to involve his entire body, sparing the palms and soles (Figures 1 and 2). His mother gave diphenhydramine at home without noticeable improvement. The evening prior to presentation, he complained of abdominal pain, refused food and water, and began vomiting, which was nonbloody and nonbilious. Review of systems was otherwise negative for altered mental status, headache, rhinorrhea, sore throat, difficulty breathing, muscle aches, swelling of hands or feet, and dysuria. He had no recent travel or trauma.In the emergency department, he was noted to be febrile (temperature 38.3 °C), tachycardic (heart rate 155), blood pressure 101/59, and hypoxic in the low 90s on room air. His physical exam was notable for microcephaly, hypertelorism, low-set ears, micrognathia, and symbrachydactyly of his hands and feet bilaterally. There was a diffuse petechial rash over his face, extremities, and trunk that spared his palms and soles. He had bilateral conjunctivitis, dry and cracked lips, and a delayed capillary refill of 3 seconds. His breathing was unlabored, and he was alert in no acute distress. Complete blood cell count with differential was normal, but inflammatory markers were elevated (erythrocyte sedimentation rate [ESR] 68, C-reactive protein [CRP] 3.2, procalcitonin 1.25). A complete metabolic panel was significant only for creatinine of 0.55 (baseline 0.3) and low bicarbonate of 18. A clean catch urinalysis was unremarkable. A chest radiograph showed diffuse bilateral patchy interstitial and airspace opacities.Notably, the patient had been admitted twice in the past 6 months for recurrent right upper lobe pneumonia. During these hospitalizations, he was found to be adenovirus and respiratory syncytial virus positive, but other infectious labs at the time were negative, including Epstein-Barr virus immunoglobulin (Ig) G/IgM, Coccidioides IgG/IgM enzyme immunoassay, cryptococcal antigen blood, Legionella urinary antigen, cytomegalovirus (CMV) IgG/IgM, and toxoplasmosis. He had numerous genetic tests done throughout his life given his dysmorphic facies and syndactyly, including whole exome sequencing; however, no underlying genetic condition was identified.Initial differential was broad considering the patient’s congenital abnormalities and chronicity of symptoms, including rheumatological/vasculitis etiology, hematological process, and infectious causes. With his fever of 2 weeks and rash as well as bilateral conjunctivitis on initial presentation, Kawasaki disease was suspected. However, he did not meet other clinical criteria. Additionally, apart from his CRP of 3.2 and ESR of 68, the remainder of his lab values did not meet supplemental laboratory criteria. The primary team also considered multisystem inflammatory syndrome in children; however, the patient had no recent history of COVID exposure and tested COVID negative upon admission. Scarlet fever was part of the differential considering the diffuse rash and persistent fever, but Streptococcus throat culture and Streptococcus antistreptolysin O were negative. Interestingly, throat culture resulted in Staph aureus, but his symptoms were inconsistent with Staphylococcal scalded skin syndrome or Staph-mediated toxic shock syndrome. Henoch-Schonlein purpura was also considered because the patient initially complained of abdominal pain and had a petechial rash without thrombocytosis, but the diagnosis was less likely because his rash was not raised and did not start in the lower extremities/buttock area and patient had no history of arthralgias.The initial leading differential was a viral pneumonia or an atypical bacterial pneumonia based on the findings from his chest radiograph. His rash was thought to be a viral exanthem.Early infectious disease workup was significant for positive CMV IgM. Subsequent initial CMV quantitative DNA polymerase chain reaction (PCR) resulted in a high viral load of 202 494 IU/mL. Curiously, petechial rashes are rarely reported as viral exanthems specific to CMV and more commonly reported in congenital CMV infections.1 Therefore, the diagnosis came as a surprise to the medical teams. A computed tomography (CT) angiogram of the chest showed diffuse septal thickening and multifocal ground glass as well as hilar engorgement of his lungs, consistent with pulmonary edema. The CT also confirmed a persistent right upper lobe segmental area of atelectasis. As the patient’s daily fevers persisted and he required increasing amounts of supplemental oxygen, CMV pneumonitis became the leading diagnosis.The patient was initially stable on room air but shortly thereafter required nasal cannula oxygen because of prolonged oxygen desaturation less than 90%. Transthoracic echocardiogram performed on hospital day 2 showed no intracardiac vegetations or mobile masses. His abdominal pain prompted an abdominal ultrasonography and abdominal radiograph that were also without acute findings.Given the persistent fever and chest radiograph findings that were indicative of a viral or atypical pneumonia, he was started on ceftriaxone and azithromycin. Subsequent tests were positive for S aureus via throat culture and CMV IgM. Chest CT and angiogram were obtained because of concern for pulmonary anatomical abnormalities in the setting of multiple prior hospital admissions for pneumonia. On hospital day 7, CMV PCR was positive with high viral load, and ganciclovir was started.Although the patient’s petechial rash improved and, later, resolved after initiation of ganciclovir, he continued to worsen from a respiratory, infectious, and hematologic standpoint. An immunology workup was initiated and showed nonprotective antibody titers despite vaccine boosters administered before admission (absent tetanus, Streptococcus pneumoniae, and Haemophilus influenzae type b titers), suggesting there was high suspicion for a humoral deficiency. His opportunistic CMV infection, low natural killer cell count, and abnormal T-cell proliferation studies indicated additional deficiencies in cell-mediated immunity. Therefore, there was highest suspicion for a combined immune deficiency (CID). Intravenous immunoglobulin (IVIG) 400 mg/kg/dose was initiated on hospital day 12 and given over 4 days (1.6 g/kg total) to augment treatment of the CMV viremia and decrease the inflammatory response. This combined therapy decreased his viral load seen on PCR by 98%. In the subsequent days, the patient’s primary problem became respiratory decompensation. A repeat CT chest showed interval increase in the diffuse ground glass opacities of the lungs. He was transferred to the Pediatric Direct Observation Unit (an intermediate level of care) given his increasing work of breathing, and a 3-day methylprednisolone course was started. Despite this intervention, the patient continued to decompensate, prompting transfer to the pediatric intensive care unit (PICU) on hospital day 30.In the PICU, the patient’s respiratory status severely deteriorated, requiring venovenous extracorporeal membrane oxygenation (ECMO) cannulation for acute-on-chronic hypoxic and hypercapnic respiratory failure hospital day 32. On hospital day 66, he began to require increasing fraction of inspired oxygen up to 100%, and ECMO settings were maximized. He had new bleeding from his endotracheal tube, and subsequent chest radiograph showed evidence of pulmonary hemorrhage and pneumothorax. The following day, the patient’s family opted for palliative extubation and removal of life-sustaining measures; the patient died quickly thereafter. An autopsy was performed and revealed lungs that were grossly, bilaterally extremely enlarged and hemorrhagic and microscopically had evidence of diffuse alveolar damage and intra-alveolar hemorrhage. Immunohistochemistry highlighted rare positive CMV in the lung, thus confirming the immediate cause of death as hypoxic respiratory failure from CMV pneumonitis with the underlying cause of death from combined immune deficiency.CMV viremia is often a self-limiting disease in immunocompetent patients, and antivirals are not usually indicated. Common manifestations may include fever, sore throat, or hepatitis on lab results. Immunocompromised hosts, most commonly transplant patients or HIV/AIDS patients, tend to have the most severe outcomes from primary CMV infections,2 including CMV retinitis, pneumonitis, and encephalitis/myelitis.2 Even with available treatment, CMV infections in immunocompromised patients have been associated with a high mortality rate or relapse.2CMV pneumonitis is a difficult diagnosis to make because symptoms and radiographic evidence are vague.3 Standard treatment consists of the antiviral ganciclovir, with or without immunoglobulins, although concurrent therapy with Ig has been shown to significantly reduce mortality in immunocompromised patients.4 Foscarnet, another antiviral, can be used as an alternative therapy, notably in patients who are neutropenic.2 Our patient was started on ganciclovir 5 mg/kg twice daily, and the need for concurrent IVIG was determined by his abnormal immunology workup. Given his phenotype of speech delay, bicuspid aortic valve, micrognathia, cleft palate, hypertelorism, and symbrachydactyly, a genetic etiology was reconsidered. Genome analysis during this hospitalization did not elucidate any pathogenic variant associated with his phenotype. One may also argue that the sequelae of his underlying pneumonia from the year prior predisposed him to lung tissue involvement with primary CMV infection. Although the specific etiology of his immunodeficiency was never determined, IVIG 400 mg/kg/dose was administered to adjunct his antiviral therapy for 4 separate treatments because of evident CID.Children with primary immunodeficiencies are at a substantial risk of morbidity and mortality due to CMV disease.5 Risk of transmission is highest in neonates because CMV can be transmitted transplacentally through genital secretions during delivery and postnatally via maternal oral secretions and breast milk.6 The rapid and relatively inexpensive T-cell recombinant excision circle (TREC) screening at birth has been beneficial in diagnosing severe congenital immunodeficiencies (SCIDs) characterized by low T cells and is becoming standard practice in US states.7 However, combined immunodeficiencies may not be identified through TREC-based SCID newborn screening programs, and a high degree of suspicion must be present for patients with persistent, recurrent, or severe infections. In the case that immunodeficiency is discovered, there may be a role for CMV prophylactic therapy because it has proven beneficial in pediatric transplant patients8; however, pediatric data are limited for nearly all aspects of CMV diagnosis and treatment.CMV is often an asymptomatic or mild self-limiting disease in immunocompetent patients; however, it can cause severe and life-threatening infection in patients with immunocompromised conditions.CMV can present as a petechial rash in an immunocompromised patient.Combined immunodeficiencies may not be identified through TREC-based SCID newborn screening programs, and a high degree of suspicion must be present for patients with persistent, recurrent, or severe infections.The treatment for suspected CMV pneumonitis in an immunocompromised patient should include early initiation of both ganciclovir and IVIG.