A 28-year-old woman was admitted to the Second Xiangya Hospital of Central South University, Hunan, China because of recurrent cough for 6 years and wheezing for 7 months, which aggravated for half a month in May 2021. The patient started to cough sputum early in September 2014, and pulmonary tuberculosis was considered the reason at the local hospital and therefore anti-tuberculosis was given. The symptoms improved significantly until 2015; the patient complained of cough with fever during the anti-tuberculosis therapy and visited our hospital for the first time. Laboratory tests showed an elevated level of leukocyte count, erythrocyte sedimentation rate, C-reactive protein level, and serum total IgE (2,500 IU/ml, normal range: <130 IU/ml). The chest CT revealed multiple cavitary lesions in both upper lungs and the dorsal segment of the left lower lung and bronchiectasis of bilateral lobes (Figure 1A). A combined infection of aspergillosis and Staphylococcus aureus was confirmed by positive culture of both sputum and bronchoalveolar lavage fluid (BALF). Anti-infection with teicoplanin and itraconazole was prescribed, and her symptoms were relieved on therapy. The patient remained stable until 2019; she began coughing intermittently and the symptoms gradually worsened when accompanied with dyspnea and wheezing. She visited our hospital for the second time in December 2020. Blood tests showed a moderately elevated level of eosinophil count (0.97 x 109/L, normal range: 0.02-0.52 x 109/L) and a markedly increased serum total IgE level (>2,500 IU/ml). Total levels of aspergillosis-specific IgE, IgM, and IgG were above normal. A pulmonary function test revealed decreased FVC (2.41 L; expected value: 2.92 L), decreased FEV1 (1.54 L, expected value: 2.53 L), and decreased FEV1/FVC (63.68%, expected value: 84.52%), indicating moderate obstructive pulmonary ventilation dysfunction and positive bronchodilation test (FEV1 increased by 16.8%). The chest CT revealed bilateral multiple bronchiectases, pulmonary bulla, and atelectasis in the right middle lung lobe (Figure 1B). Based on these data, a diagnosis of allergic bronchopulmonary aspergillosis (ABPA) was made. Oral voriconazole 200 mg two times daily and methylprednisolone 16 mg per day plus inhaler were prescribed but were demonstrated to be insufficient without the improvement of symptoms. Since February 2021, she was given omalizumab 600 mg three times every month; she was readmitted due to the aggravation of cough and wheezing. The patient denied any history of food or drug allergies. Her family history was negative for any inherited genetic diseases.
On physical examination, her body weight was 58 kg on admission. She exhibited facial flushing, a full moony face, buffalo back, and mossy skin changes on the scalp. Moist rales could be heard on bilateral lung fields. Her laboratory findings on admission revealed moderate C-reactive protein level (33.6 mg/l, reference range: 0-6 mg/l) and a normal level of leukocyte count and erythrocyte sedimentation. Serum IgE was above normal (770 IU/ml, reference range: <130 IU/ml); serum -beta-D-glucan test, galactomannan test, anti-nuclear antibody, anti-neutrophil cytoplasmic antibodies, vasculitis antibodies, antiphospholipid antibodies, antibodies to extractable nuclear antigens, and rheumatoid factor were negative. Pulmonary CT suggested diffuse multiple ground glass shadows and scattered striae in both lungs and more cystic lesions than previously observed (Figure 1C). Bronchoscopy showed viscous jelly-like secretions in the tracheal lumen. The next-generation sequence (NGS) of BALF indicated Pneumocystis jirovecii (sequence reads 34909), Human Herpes Virus Type 5 (also named CMV, sequence reads 1843), and Human Herpes Virus Type 4 (also named EBV, sequence reads 7). With classic diffuse ground-glass lesions appearing in the chest CT images and high sequence reads of CMV and P. jirovecii in BALF detected by mNGS, we identified that the patient had CMV and P. jirovecii coinfection. The sequence reads of EBV, which is ubiquitous in most of the population, were too few to be identified as pathogenic. SMZ-TMP and ganciclovir were given and symptoms were gradually relieved (Figure 2).
Given that the young patient was predisposed to multiple pathogens, including some opportunistic strains, we carefully reviewed the patient's medical history. Surprisingly, she had multiple skin rashes and pruritus all over the body since childhood. A minor traumatic fracture of the right calf occurred at the age of 12. She underwent cutaneous abscesses requiring incision and drainage at 13 years of age. The patient also had a previous diagnosis of pelvic abscess, tubal occlusion, and primary infertility. The patient had recurrent infections of different strains including opportunistic pathogens in multiple organs, skin rashes, and markedly elevated IgE levels. HIES were suspected, and she scored 45 points on the National Institutes of Health clinical HIES scoring system. Further whole-exome sequencing (WES) was performed to screen potential mutations, indicating a heterozygous missense mutation in exon 15 of STAT3 (c.1294G>T, g.62382G>T, p.Val432Leu, NM_139276.2). Consequently, the final diagnosis was made as AD-HIES. Her parents and younger sister are wild-type genotypes. In addition to the standard anti-infection therapy, we prescribed omalizumab 300 mg every 2 weeks and Seretide inhalation. Oral corticosteroids gradually reduced and stopped. During 6 months of follow-up, the patient did not experience recurrent infection. After an initial fluctuation of the level, serum IgE remained stable recently. The patient's symptoms and lung function improved on therapy (Figure 3). The chest CT scan demonstrated improved infiltrates (Figure 1D).
Pulmonary imaging by CT scan. (C) 8 May 2021: diffuse multiple ground glass shadows and scattered striae in both lungs and more cystic lesions than previously observed.