Nosocomial Transmission of Human Granulocytic Anaplasmosis?

In this issue of JAMA, Zhang and colleagues describe a possible nosocomial outbreak of human granulocytic anaplasmosis (HGA) in China.¹ The clinical presentation of the index case, a previously healthy 50-year-old woman who developed a febrile illness with rash and massive bleeding and who died 5 days later, is consistent with many infectious etiologies including viral hemorrhagic fever (VHF) for which she was given ribavirin.² Laboratory studies in 9 subsequent cases in family members and health care workers who had contact with the patient, however, suggested that her disease was HGA.

Human granulocytic anaplasmosis is an emerging tick-borne infectious disease caused by Anaplasma phagocytophilum that occurs in Lyme disease–endemic areas in the United States and sporadically in Europe. Clinical manifestations of HGA are usually mild to moderate and most patients promptly respond to treatment with doxycycline, which neither the index patient nor the subsequent cases in this report received. Spontaneous resolution of HGA without antibiotic therapy also is well documented.^{3 - 4} Headache occurs in about three-quarters of cases of HGA, but diarrhea and rash are infrequent, and relative bradycardia has not been reported.^{3 ,5} Deaths from HGA occur in less than 1% of those infected and typically involve elderly persons or those who are immunocompromised, usually 10 or more days after disease onset.^{3 ,6}

In the outbreak described by Zhang et al, the index case and all 9 of the secondary cases experienced fever with relative bradycardia, 7 had diarrhea, and 3 had headache. Thus, some of the clinical findings in these cases were atypical for HGA. The index case had a tick bite but also had exposure to mice and other animals before the onset of illness and therefore was at risk of a variety of infections. Transmission to the secondary cases most likely occurred through cutaneous or mucous membrane contact with blood or bloody respiratory secretions during a 12-hour period in the critical care unit when the index case underwent endotracheal intubation. In China, family members provide bedside care and so were present at the time of the patient's intubation and final hours. Use of personal protective devices such as gowns, gloves, or masks is sporadic at best. This could set the stage for transmission in a manner that would be unlikely in the United States.

Human granulocytic anaplasmosis replicates in neutrophils and can be transmitted by blood inoculation in experimental animals.⁷ There is also limited evidence for transmission to humans through blood transfusion.^{5 ,8 - 9} In a published report from the upper Midwest, 3 adults who had each recently butchered more than 250 deer and gave no report of tick bites developed HGA, possibly because of exposure to deer blood.¹⁰ Recent molecular microbiological studies, however, suggest that the strain of A phagocytophilum present in deer blood is a variant that has thus far not been documented to cause infections in humans.^{11 - 12} A plausible alternative explanation is that these individuals were unknowingly bitten by ticks that they encountered on the deer carcasses. Ixodes scapularis ticks were present on all 66 deer examined in one study from Westchester County, New York.¹³

In the report by Zhang et al, the index case died before antibody against A phagocytophilum would likely have been detectable and no residual blood or other tissue was available for postmortem polymerase chain reaction (PCR) testing. Among the secondary cases, the reported laboratory tests support the diagnosis of HGA. Amplification of A phagocytophilum HGA DNA was observed in all of the secondary cases and was further confirmed by direct nucleotide sequencing. DNA of A phagocytophilum can be detected in blood by PCR in about three-fourths of patients with HGA in the United States.¹⁴ As Zhang et al report, the genetic analysis revealed nucleotide sequences that more closely resembled a US strain of A phagocytophilum than strains known to exist in China, although the implications of this observation are unclear. A limitation of the outbreak investigation is that neither blood smears nor blood cultures for A phagocytophilum were reported to be positive.

Seroconversion against A phagocytophilum antigen was demonstrated by indirect immunofluorescence assay (IFA) in all the secondary cases and a 4-fold increase in antibody titer was found in 7 of the 9 patients. The maximum antibody titers were less than or equal to 1:256 in convalescent-phase samples, values that are lower than commonly observed in culture-confirmed cases of HGA in the United States where the titer is greater than or equal to 1:640 in more than 95% of seropositive patients.¹⁵ In a study from New York, the majority of unexplained low-titer IFA-positive results from serum samples could not be confirmed when retested by immunoblot, but that study population consisted of healthy blood donors rather than patients with an illness suspected to be HGA.¹⁶ The relatively low antibody titers observed in the Chinese outbreak might have resulted from infection with a strain of A phagocytophilum that differed from the one used for antigen preparation. Differences of this magnitude, however, were not commonly observed in studies from the United States that have compared different strains of A phagocytophilum used as antigen.^{15 ,17} It is unclear whether differences in the strains of A phagocytophilum between those found in China and those found in the United States and Europe might account for some of the other unusual clinical and epidemiological findings in this outbreak. More research on the implications of strain diversity is needed.

What is the significance of the investigation by Zhang et al? It may represent the first report of human-to-human transmission of A phagocytophilum and the first report of human HGA infection in China. This report certainly serves to reinforce the importance of adopting standard blood and body fluid precautions for all patients and especially for those with HGA; these precautions are the accepted standard of care in the United States. The report also should stimulate further investigation of the existence of A phagocytophilum in the region of China where this outbreak originated. In addition, it is essential to emphasize that fulfilling the case definition of HGA used for epidemiological surveillance in the United States does not provide diagnostic certainty, unless the diagnosis was established by the microbiological gold standard of culturing the microorganism. Therefore, the findings of the study by Zhang et al, while interesting and provocative, should be regarded as preliminary.