Yellow fever is an infectious disease, endemic in tropical areas in America and Africa. According to the monitoring of the seasonal period of yellow fever in Brazil, from July 2017 to March 2018, 4414 suspected cases of yellow fever were reported in humans, with 1131 confirmed cases (25.6%) and 338 deaths, a case fatality rate of 29.9%.1 Here we report a case that the wild-type (WT) yellow fever virus (YFV) was detected in a breast milk sample.
A 33-year-old woman, from a rural area in the municipality of São Paulo, State of São Paulo, Brazil, with no comorbidities, no previous yellow fever vaccine and breast-feeding a 6-month-old daughter, was admitted to the Institute of Infectology Emilio Ribas with fever, headache and malaise for 3 days. She had used analgesics with partial improvement but relapsed in the following days. At admission, she was clinically stable, prostrated and showing relevant alterations in laboratory parameters: leukocytes 2800/mm3, platelets 103,000/mm3, aspartate aminotransferase (AST) 3108 U/L, alanine aminotransferase (ALT) 2189 U/L and international normalized ratio (INR) 1.35. The infant was also admitted with high fever, vomiting and prostration, with leukocytes 10,500/mm3, platelets 599,000/mm3, INR 1.22, urea 28 mg/dL, total bilirubin 0.86 mg/dL, AST 71 U/L, ALT 19 U/L and urinalysis with leukocyturia (104 mil/mL). The mother was then transferred to an intensive care unit with suspected yellow fever and the infant to the pediatric ward, later being transferred to the pediatric referral hospital, where he presented rapid resolution of the symptoms remaining uneventful until hospital discharge. Blood and breast milk samples from the mother (fourth day of symptoms)and blood samples from the infant (first day of symptoms) were collected for real-time reverse transcription-polymerase chain reaction (RT-PCR) detection of the YFV. During the collection of the samples, the patient was evaluated by clinical examination and there was no evidence of areolar lesion or contamination of the breast milk by blood.
The viral nucleic acid was extracted from 140 µL of serum using a QIAmp viral RNA Minikit (Qiagen, Hilden, Germany) and from 500 µL of milk with a PureLink Viral RNA/DNA Minikit (Invitrogen, Thermo Fisher Scientific, Waltham, Massachusetts, USA), according to the manufacturer’s instructions.2 Initially, the extracted RNA is submitted to the protocol which amplifies a noncoding region of the 5′ end of the virus, being conserved among the different strains. This protocol can detect both the WT virus genome and the vaccine-virus genome. The positive samples in the first reaction are submitted to a reaction for differentiation between wild and vaccine viruses. In this second stage, a new real-time RT-PCR is performed, which detects only the vaccine virus. Therefore, samples with a positive result in the first reaction and negative in the second reaction are considered positive for wild virus. Positive samples in both reactions are considered positive for vaccine virus.
On the following day, the mother clinically improved, despite the worsening of some laboratory abnormalities: leukocytes 2700/mm3, platelets 101,000/mm3, AST 5783 U/L, ALT 3162 U/L and INR 1.58. On consecutive days, she remained asymptomatic, without hemorrhagic manifestations, jaundice, worsening renal function or neurologic impairment and presented improvement in liver markers with a progressive and gradual decrease in transaminases and normalization of INR. She was discharged from the intensive care unit after 5 days with improvement in all laboratory parameters. The patient then remained asymptomatic in the ward for 7 days with progressive improvement of laboratory parameters receiving hospital discharge. The WT YFV genome was detected in both samples (breast milk and blood) from the mother, thus confirming the diagnosis, but was undetectable in the serum sample from the infant, using RT-PCR. It was recommended that breast-feeding be suspended from admission to the hospital.
Breast-feeding is widely recognized as the best way to feed infants <2 years of age. However, it is implicated in the transmission of various pathogens such as bacteria, viruses and parasites. In the case of viruses, viral hepatitis, caused by HAV, HBV and HCV, herpes virus, CMV and retroviruses (HIV-1, HTLV 1 and 2) are transmitted through breast milk and the transmission potential is significantly increased during the acute phase of the illness at the time of delivery so that high levels of virus particles occur in milk with low titers of neutralizing antibodies.3 Traditionally, HIV and HTLV infections are permanent contraindications to breast-feeding. In the case of herpes simplex, the contraindication occurs only in the presence of lesions on the breast. In acute chickenpox infection, breast-feeding is contraindicated if the infection occurs 5 days before and 3 days after delivery. In other viral infections, there is no contraindication to breast-feeding, either because there are effective measures to avoid transmission, as in the case of HAV and HBV, or because breast milk is not an important form of transmission.4
Regarding Flaviviruses, a recent systematic literature review found 19 cases in the literature with virus detection in breast milk through PCR, 6 cases of Zika, 10 cases of Dengue and 3 cases of West Nile. No case of yellow fever was found. On the subject of possible transmissions through breast-feeding, 7 possible/probable cases were found, including 1 of Zika, 2 of dengue, 2 of West of Nile and 2 of yellow fever. They also found 1 case of yellow fever confirmed by nucleotide sequencing. All 3 cases of yellow fever were related to the vaccine’s variant of the virus, and in none of the reported cases was the presence of the virus in breast milk detected.9 In all 3 cases, the infants presented a similar clinical presentation with fever and tonic-clonic seizures and were being breast-fed after vaccination. In the case confirmed by PCR in the cerebrospinal fluid of the infant, the mother was vaccinated when the infant had 15 days of life and the disease started with 23-day of life. In the other 2 cases, IgM antibodies for YFV were detected in serum samples and one of the infants also had IgM antibodies in the cerebrospinal fluid. In this case, the mother was vaccinated when the infant presented 14 days of life with the condition starting at 38 days of age. In the other, the infant had 10 days of life at the time of vaccination and 5 weeks of life at the opening of the clinical presentation. We also found in the literature 2 reports of cases of perinatal transmission of yellow fever confirmed by PCR. However, one of the cases did not have breast-feeding.10 Both newborns had a systemic clinical presentation presenting seizures probably secondary to hepatic failure. These cases exemplify the characteristic neurotropism of YF vaccine virus in contrast with the more systematic impairment caused by the WT YF virus.
After careful searching in most of the major databases in US National Library of Medicine-Pubmed, we did not find a similar study or report, showing, as we did, evidence of the presence of YFV at breast milk, thus highlighting a potential risk for transmission of YFV through breast-feeding. Nevertheless, since the YFV genome was not detected in the infant serum, this hypothesis cannot be confirmed; thus, raising the value of new research on the subject.
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