Puel et al. describe two kindreds with factor D deficiency. Two affected patients presented with invasive infections with encapsulated bacteria, one individual was still asymptomatic. The authors emphasize two aspects in their report: (1) The presence of Down’s syndrome should not prevent from evaluating individuals with severe invasive infections from other genetic causes of immunodeficiency and (2) Despite initial signals of safety, novel MASP-3 or FD inhibitors should be receive preventive measures against severe infections with encapsulated bacteria.

While there are no novel immunological or mechanistic insights from these patients, there are some relevant clinical aspects. The following points may help to further elaborate this clinical message:

1. The introduction carefully summarizes the role of Factor D in the complement pathway, but does not mention the clinical symptoms associated with it. Since the focus of the paper is clinical and not the function of the complement cascade, the clinical aspects should be better introduced.
2. The authors stated that they performed a literature review. It would be helpful, if the details of this review could be presented in a (supplementary) table. Age at onset of first invasive infection (or age of last report in asymptomatic individuals), pathogen, further clinical course, outcome
3. Vaccination status for meningococcal and hemophilus infection should be mentioned
4. I am not sure I understood correctly: P2 is now 16 and has been asymptomatic for the 8 years following the meningococcal sepsis?
5. The cousin of P2 is only briefly mentioned. Age? Vaccination status? Infection history?
6. “Disturbed” T cell subpopulations are mentioned in P1. What does this mean?
7. “detectable but decreased serology to protein antigen” – what exactly - be more precise.
8. In the discussion, several asymptomatic patients are mentioned. What was their age at the last report?
9. Line 203: “absence of infection with encapsulated bacteria” – by the age of 7-8, children will have had contact with encapsulated bacteria and also may have had infections with these pathogens. Here you probably mean “invasive” infections?
10. Line 217: severe encapsulated genes infections? What do you mean with genes?

The authors have well addressed all my concerns.