Patient 1
A 31-year-old woman with a twin pregnancy experienced fever, dry cough, and colporrhagia 5 weeks after embryo transfer. After the symptoms had persisted for 2 months, she was transferred to our hospital on January 13, 2017. She denied any history of exposure to or infection with TB; moreover, she had undergone four IVF-ET treatments for inflammation-induced oviduct obstruction.
Baseline vital parameters were as follows: blood pressure, 101/64 mmHg; pulse, 134/min; respiratory rate, 42/min; and body temperature, 40°C. The patient presented with cyanosis and shortness of breath, with vesicular breath sounds under the lung fields on auscultation. Arterial blood gas analysis revealed type I respiratory failure and respiratory alkalosis. Table 1 shows the important laboratory results during hospitalization. Serum and sputum cultures were negative for bacteria, fungi, and viruses. Chest radiography (Fig. 1. a) revealed diffuse reticular nodules; moreover, chest computed tomography (CT, Fig. 1.c) revealed bilateral diffuse ground glass shadows and miliary nodules as well as spotted calcification in the upper left lung, which was consistent with miliary TB. Further examination showed that the interferon-gamma test was positive. The tuberculin purified protein derivation test was strongly positive. However, bronchoalveolar lavage was negative for acid-fast bacilli. General assessment revealed no extrapulmonary TB locations. International guidelines established by the American Thoracic Society recommend that patients with TB who are etiologically negative but have positive clinical/radiographic findings should receive standard anti-TB therapy (ATT) [10]. Accordingly, she was started on five-drug ATT, which included isoniazid (INH, 0·3 g/day), rifampicin (RIF, 0·45 g/day), pyrazinamide (PZA, 1·5 g/day), and ethambutol (EMB, 0·75 g/day) plus moxifloxacin (Mfx, 0·4 g/day).
Table 1
Summary of clinical characteristic of the three patients and their results during the hospitalization.
Characteristic | Patient 1 | Patient 2 | Patient 3 |
Summary of features | Age(years) | 31 | 30 | 26 |
Onset time of symptoms at pregnancy(weeks) | 5 | 12 | 11 |
TB1history | Denial of TB1 history | Denial of TB1 history | Close exposure to TB1* |
Onset manifestation | Fever, dry cough and colporrhagia | Fever, headaches and cough | Fever, headaches, double vision, and shortness of breath |
Diagnosis | Miliary pulmonary TB1 | Disseminated TB1 | Tuberculous meningitis |
Outcomes for fetus | Spontaneous abortion | Spontaneous abortion | Spontaneous abortion |
Abortion time at pregnancy(weeks) | 16 | 16+ 3 | 15 |
Pregnancy outcomes for pregnant women | Cured | Cured | Cured |
Laboratory results (First day of admission) | WBC (× 109/L) (3.5–9.5) | 5.5 | 6.1 | 4.9 |
Hb(g/L) (115–150) | 83 | 97 | 119 |
PLT (× 109/L) (125–350) | 212 | 290 | 194 |
N% (40–75) | 85.5 | 89.1 | 69.5 |
ALT(U/L) (20–50) | 32.6 | 16.5 | 35.5 |
AST(U/L) (13–35) | 98.7 | 33.3 | 33 |
TB2(µmol/L) (1.7–17.1) | 14.9 | 2.1 | 7.9 |
A(g/L) (40–55) | 25.9 | 25.5 | 34.3 |
K+(mmol/L) (3.5–5.3) | 3.49 | 3.44 | 3.9 |
CRP (mg/L) (0–8) | 41.3 | NA | NA |
ESR (mm/h) (0–26) | 16 | 54 | 45 |
PCT (ng/ml) (< 0.05) | < 0.05 | 0.17 | < 0.05 |
TB1-related | T-SPOT.TB | + | + | + |
PPD test | +++ | NA | NA |
Xpert MTB/RIF | NA | +(CSF) | +(CSF) |
Sputum culture | – | NA | NA |
Blood culture | – | – | – |
CSF culture | NA | – | – |
Cervical secretions culture | NA | Mtb, Prevotella bivia | NA |
Acid-fast staining | NA | + (cervical secretions) | +(CSF) |
NA = Not available. +=positive. –=negative.TB1 = tuberculosis. WBC = white blood cell. Hb = hemoglobin. PLT = platelet. N%= percentage of neutrophils. ALT = alanine aminotransferase. AST = aspartate aminotransferase. TB2 = total bilirubin. A = albumin. K+= serum potassium ions. CRP = C-reactive protein. ESR = erythrocyte sedimentation rate. PCT = procalcitonin. T-SPOT.TB = Tuberculous infection of T cell spot test. PPD = purified protein derivative. Mtb = Mycobacterium tuberculosis; CSF = cerebrospinal fluid. |
*The father of Case 3 infected with TB and was cured after ATT 10 years ago. |
After approximately 1 week of ATT, there was a decrease in the patient’s maximum body temperature (Fig.S1) and an improvement in blood oxygen saturation. Chest radiography (Fig. 1. b) and CT (Fig. 1. d) showed improvement in diffuse, bilateral, and discrete miliary nodules on week 3 of ATT. At 16 weeks of pregnancy, vaginal bleeding worsened and she underwent induced abortion. Meropenem (Mem) was used to prevent intrauterine infections. Owing to severe liver damage, RIF and PZA were discontinued and replaced with linezolid (Lzd) and rifapentine (Rpt). However, Lzd was discontinued because of frequent vomiting. Fig.S1 shows the changes in clinical symptoms and the highest body temperature with adjustment of antibiotics during hospitalization.
The patient was discharged home on February 22 with a follow-up appointment in specialized TB hospitals. She was maintained on treatment with oral INH (0·3 g/day), EMB (0·75 g/day), Rpt (0·45 g, twice a week), and levofloxacin (0·5 g/day) for approximately 6 months. The patient was completely cured without sequelae and she underwent IVF-ET again without any additional complications. Finally, she gave birth to a healthy son.
Patient 2
A 30-year-old housewife conceived by IVF-ET owing to a fallopian tube obstruction. At 12 weeks of pregnancy, the patient began experiencing persistent headaches, cough, and sputum with low-grade fever (37·5℃–38·5℃). She denied a history of TB or exposure to TB. During pregnancy, she received 10 mg of oral dydrogesterone. At 16 gestation weeks, she was admitted to our hospital with extreme thinness, unclear consciousness, and positive meningeal stimulation. Additional examination revealed vesicular breath sounds under the lung fields on auscultation, a full abdomen with left-upper tenderness, and slight colporrhagia.
Table 1 shows important laboratory results at admission. The T-SPOT. TB test was highly positive for ESAT-6 and CFP-10, with both having test values > 50 (reference normal value: < 6). The cerebrospinal fluid (CSF) was slightly turbid in appearance, with an opening pressure of 230 mmH2O, polykaryocyte predominance (80%), hypoglycorrhachia (1·98 mmol/L), proteinorachia (0·66 g/L), and lower chloride (119·8 mmol/L), which was consistent with TB meningitis (TBM). Examination using Xpert MTB/RIF Ultra confirmed Mtb in the CSF, without evidence of RIF resistance. There were no organisms in the CSF on the Gram stain, Ziehl–Neelsen stain, or ink stain tests. Blood and CSF cultures were negative for bacteria and fungi. Additionally, microscopic examination of acid-fast bacilli in cervical secretions revealed positive results; moreover, Mtb and Prevotella bivia were cultivated in cervical secretions. Chest and abdominal CT revealed bilateral diffuse miliary nodules as well as diffuse peritoneal and mesenteric thickening, which further supported the diagnosis of acute miliary TB and TB peritonitis. Brain magnetic resonance imaging (MRI) revealed multiple abnormal signal foci, which suggested that TB encephalitis was more likely.
Accordingly, the patient was diagnosed with disseminated TB. She was started on ATT, which comprised INH (0·6 g qd), RIF (0·45 g qd), PZA (1·5 g qd), EMB (0·75 g qd), and streptomycin (0·75g qd). On the third day of admission, the patient presented with persistent fever (up to 40°C) and heavy vaginal bleeding, which was diagnosed as an inevitable miscarriage. Accordingly, she urgently underwent pregnancy termination. Metronidazole tablets (500 mg) were administered thrice daily to prevent postpartum intrauterine infection. The condition of the patient further deteriorated and she was transferred to a TB specialist hospital on January 10.
Despite her serious illness, we learned that the patient was recovering well and had discontinued TB-related drugs one and a half years after discharge.
Patient 3
A 26-year-old woman who presented with fever accompanied by headaches, double vision, and shortness of breath at 11 weeks of pregnancy conceived by IVF-ET. Ten years ago, the patient’s father had been infected with TB and had been treated using ATT. Physical examination revealed a clear consciousness, normal limb muscle strength, normal muscle, positive Babinski's reflex, and positive meningeal stimulation. The other physical observations were unremarkable.
After admission, the patient's body temperature fluctuated between 38°C and 40°C (Fig. S2). Table 1 shows the laboratory results during hospitalization. No organisms were detected in the blood, bone marrow, and CSF. There were positive results in the interferon-gamma release assay. The CSF of the first spinal tap showed a light-yellow turbid appearance and an opening pressure of > 500 mmH2O. CSF analysis revealed polynucleosis, reduced glucose levels (0·89 mmol/L), reduced chlorine levels (104·8 mmol/L), and remarkably increased protein levels (2·69 g/L) (Table S1). Moreover, biochemical analyses revealed a substantial increase in the levels of adenosine deaminase (11·4 U/L) and lactate dehydrogenase (408 U/L (Table S1). Lumbar CSF was positive for Mtb through acid-fast staining and the X-pert assay, with no evidence for RIF resistance. Brain MRI revealed nodules in the anterior horn of the left ventricle and multiple intracranial pial enhancements, which was consistent with TB infection (Fig. 2).
All these test results led to the clinical diagnosis of TBM. RIF (0·45g/d), INH (0·9g/d), PZA (1·5g/d), and EMB (0·75g/d) were used as an ATT. The patient underwent four-drug chemotherapy; however, she still presented fever (Fig.S2). Therefore, Mem (6 g/d, June 7 to June 14) was used for TBM treatment since it penetrated the blood–brain barrier [11]. Subsequently, the temperature gradually normalized. Repeated lumbar punctures showed dynamic fluctuations in the intracranial pressure, protein levels, chlorine, and the proportion of multinucleated cells (Table S1). CSF protein was still at a high level; therefore, Lzd (1·2g/d) was added to the TB therapy on June 23. The patient was discharged on June 24 upon request by her family.
We learned that the patient experienced an inevitable miscarriage one week after discharge. Follow-up lung and brain CT scans at 1 year after diagnosis revealed complete regression of all lesions as well as normal liver and kidney function, without pregnancy. The patient is still undergoing RIF, EMB, and Mfx at the latest follow-up in July 2022.